Scientists have discovered an unmistakable language within all living things. Like a miniature library, DNA stores piles of information in extraordinary molecules that specify the details of everything from the shape of flower petals to the color of your eyes. A supremely intelligent Author and Life-Giver left His indelible message in every living thing.

The species on earth today descend from the original created kinds of Genesis 1. The many inter-species breedings that are possible today (e.g., zonkeys, wholphins), as well as the close similarities within biological groups (e.g., the canine group) that are distinct from one another, remind us of this fact. But exactly why the created kinds have fractured into many incompatible species has only been answered indirectly by creationists.

Successful evolution requires the addition of new information and new genes that produce new proteins that are found in new organs and systems. Losing structures, or misplacing their development, should not be equated with the increased information that is needed to form novel structures and cellular systems.

Minimal genomes is the number of genes considered essential for a bacterium to survive in a nutrient-rich, stress-free and competitor-free environment in the lab. Evolutionists believe if the genes universal to all life can be determined then its just a matter of tinkering with the existing genetic information via mutations to go from goo to you.

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Genetics | Answers in Genesis

Females calving heifers in their first two pregnancies produce up to 981 lbs. more milk over the two lactations than females calving back-to-back males.

(Hinde K, et al, (2014), Holsteins Favor Heifers, Not Bulls: Biased Milk Production Programmed during Pregnancy as a Function of Fetal Sex. PLoS ONE 9(2): e86169. doi:10.1371/journal.pone.0086169)

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ST genetics

The Division of Genetics at Advocate Medical Group offers a team of genetic specialists to help individuals and families navigate the complex arena of genetics and genomics. We are committed to the diagnosis, management, and treatment of patients with genetic disorders.

Our specially trained clinical geneticists and genetic counselors provide a full range of services including:

We guide families facing hereditary and genetic disorders through complicated genetic issues in an easy-to-understand manner and provide educational resources helpful to your understanding of a genetic disorder. Our specialists can also help you identify support groups and social services, and coordinate and refer you to appropriate specialty providers based on your diagnosis.

The Division of Genetics offers comprehensive care that extends beyond genetic counseling and diagnosis. Our patients have access to multidisciplinary clinics that offer exceptional, compassionate care to children and adults with a variety of genetic disorders. Individuals in these multidisciplinary clinics have the opportunity to be evaluated by an experienced treatment team which includes multiple specialists from different healthcare disciplines.

Our specialists will determine which genetic tests are most appropriate for your particular situation. We discuss the risks, benefits, and limitations of genetic testing, as well as the emotional issues of a diagnosis and knowing your risk.

The Advocate Medical Group Genetics offers a range of services.

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Genetics - Advocate Health Care

Top-Ranked Genetics Department

The Department of Molecular and Human Genetics at Baylor College of Medicine is ranked first in the countryin grants and funding from the National Institutes of Health.

The Department has launched Consultagene, a newand innovative virtual platform for genetics services.Find out more about it here.

Baylor Miraca Genetics Laboratories, a joint venture of Baylor College of Medicine and Miraca Holdings, Inc., has rebranded as Baylor Genetics.

Baylor College of Medicine centers, ledby Drs. Richard Gibbs, James Lupski, and Suzanne Leal, will receivefunding as a result of programslaunched today by the National Human Genome Research Institute.

The Department of Molecular and Human Genetics is participating in anNIH-sponsored, multi-center study called the Undiagnosed Disease Network. The program is currently accepting online applications.

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Molecular and Human Genetics | Baylor College of Medicine ...

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term variant rather than the term mutation to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2016, about 62,700 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 14,240 deaths.[1] This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1.[2] RCC is distinct from kidney cancer that involves the renal pelvis or renal medulla, and it only applies to cancer that forms in the lining of the kidney bed (i.e., in the renal tubules). Genetic pathogenic variants have been identified as the cause of inherited cancer risk in some RCC cancerprone families; these pathogenic variants are estimated to account for only 1% to 2% of RCC cases overall.[3] It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors. About 80% of sporadic RCC is of clear cell histopathology.[2] Nonrenal cell cancers of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary.

RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inherited RCC syndromes have been identified:

These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on Renal Cell Cancer Treatment and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)

The natural history of each of the RCCs varies according to the characteristic histopathology of the renal tumors that arise in the specific syndrome. Although it is useful to follow the predominant reported natural history of each syndrome, each individual affected will need to be evaluated and monitored for occasional individual variations. The individual prognosis will depend upon the characteristics of the renal tumor at the time of detection and intervention and will differ for each syndrome (VHL, HPRC, BHD, and HLRCC). Prognostic determinants at diagnosis include the stage of the RCC, whether the tumor is confined to the kidney, primary tumor size, Fuhrman nuclear grade, and multifocality.[4-6]

RCC accounts for about 4% of all adult malignancies in the United States.[7] Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease. The relative risk (RR) is estimated to be 2.5 for a sibling of an RCC-affected patient.[8-10] Analysis of renal carcinomas up to the year 2000 in the Sweden Family-Cancer Database, which includes all Swedes born since 1931 and their biological parents, led to the observation that risk of RCC was particularly high in the siblings of those affected with RCC. The higher RR in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[8] Investigators in Iceland studied all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). In addition, they used an extensive computerized database to perform a unique genealogic study that included more than 600,000 Icelandic individuals. The results revealed that nearly 60% of RCC patients in Iceland during this time period had either a first-degree relative or a second-degree relative with RCC.[9] A study that evaluated 80,309 monozygotic twin individuals and 123,382 same-sex dizygotic twin individuals in Denmark, Finland, Norway, and Sweden found an excess cancer risk in twins whose co-twin was diagnosed with cancer.[11] The estimated cumulative risks were an absolute 5% higher (95% confidence interval [CI], 4%6%) in dizygotic twins (37%; 95% CI, 36%38%) and an absolute 14% higher (95% CI, 12%16%) in monozygotic twins (46%; 95% CI, 44%48%)for twins whose co-twin also developed cancerthan that in the overall cohort (32%). Overall heritability of cancer, calculated by assessing the relative contribution of heredity versus shared environment, was estimated to be 33%. Heritability of kidney cancer was estimated to be 38% (95% CI, 21%55%), with shared environmental factors not showing a significant contribution to overall risk.

Young age at onset is also a clue to possible hereditary etiology. In contrast with sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of kidney cancer are generally diagnosed at an earlier age. In a review from the National Cancer Institute of over 600 cases of hereditary kidney cancer, the median age at diagnosis was 37 years, with 70% of the cases being diagnosed at age 46 years or younger,[12] compared with a median age at diagnosis of 64 years in the overall population.[13]. Bilaterality and multifocality are common in most heritable RCC, except in HLRCC.

There is no consensus regarding whom to refer for genetic consultation for a possible hereditary kidney cancer syndrome, although the following organizations have offered guidance:

Studies of environmental and lifestyle factors contributing to the risk of RCC focus almost exclusively on sporadic (i.e., nonhereditary) RCC. Smoking, hypertension, and obesity are the major environmental and lifestyle risk factors associated with RCC.[16] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to somatic variants in the VHL gene.[17] Dietary intake of vegetables and fruits has been inversely associated with RCC. Greater intake of red meat and milk products have been associated with increased RCC risk, although not consistently.[18]

Four major heritable renal cell cancer (RCC) syndromes (von Hippel-Lindau syndrome [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dub syndrome [BHD], and hereditary papillary renal cancer [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following sections of this summary.

Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major RCC syndromes. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for VHL, BHD, HLRCC, and HPRC. Genetic counseling is a prerequisite for genetic testing. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Von Hippel-Lindau syndrome (VHL) (OMIM) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHL gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system (CNS) hemangioblastomas, retinal angiomas, clear cell RCCs (ccRCCs) and cysts, pheochromocytomas, cysts and neuroendocrine tumors (NETs) of the pancreas, endolymphatic sac tumors (ELSTs), and cystadenomas of the epididymis (males) and of the broad ligament (females).[1,2,13,14] A multidisciplinary approach is required for the evaluation, and in some cases the management, of individuals with VHL. Specialists involved in the care of individuals with VHL may include urologic oncology surgeons, neurosurgeons, general surgeons, ophthalmologists, endocrinologists, neurologists, medical oncologists, genetic counselors, and medical geneticists.

The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.[15] VHL pathogenic variants occur in all three exons of this gene. Most affected individuals inherit a germline pathogenic variant of VHL from an affected parent and a normal ("wild-type") VHL from their unaffected parent. VHL-associated tumors conform to Knudsons two-hit hypothesis,[16,17] in which the clonal origin or first transformed cell of the tumor occurs only after both VHL alleles in a cell are inactivated. The inherited germline pathogenic variant in VHL represents the first "hit," which is present in every cell in the body. The second hit is a somatic pathogenic variant, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, VHL allele, creating a clonal neoplastic cell of origin, which then proliferates into a tumor mass.

The prevalence of VHL has been estimated to be 1 per 35,000 and 1 per 40,000 persons in the general population.[18,19] Thus, the number of VHL-affected individuals in the United States is estimated at between 6,000 and 7,000. Precise quantification of this number is a challenge because it requires comprehensive screening of potentially at-risk blood relatives of individuals diagnosed with VHL. Within this population, the large number of unique pathogenic variants in this small three-exon gene indicates that most family clusters have not arisen from a single founder. A founder effect was reported when a large U.S. family was compared with a family in Germany, both of whom had pheochromocytoma-predominant VHL.[20]

VHL pathogenic variants are highly penetrant and overall penetrance is greater than 90% by age 65 years.[18] Almost all carriers develop one or more types of syndrome-related neoplasms.

Each offspring of an individual with VHL has a 50% chance of inheriting the VHL pathogenic variant allele from their affected parent. The primary factors affecting the chances of developing VHL are: 1) a relative with VHL; 2) a germline pathogenic variant in the VHL gene; 3) a family member with one of the manifestations of VHL (e.g., CNS hemangioblastomas). (Refer to the Genetic diagnosis section of this summary for more information.)

There are a few highly predictive, direct genotype -phenotype correlations.[21,22]

For example, pheochromocytoma without RCC is the VHL pattern found in a large family with a single nucleotide change at position 505.[14,21,23] A similar family outside the United States was identified and found to have a common ancestor (i.e., a founder pathogenic variant).[23] However, no common ancestor was identified for several other pathogenic variants that occurred in multiple families. In general, founder pathogenic variants do not comprise a significant fraction of all VHL variants. Single nucleotide changes at position 712 and 713 are hot spots for pathogenic variants leading to pheochromocytomas.[23] Pathogenic variant types leading to clinical VHL include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variants of VHL.

When a VHL diagnosis is made in an individual whose ancestors (biological parents and their kindred) do not have VHL, this may result from a de novo (new) VHL pathogenic variant in the affected individual. Patients diagnosed with VHL, who have no family history of VHL, have been estimated to comprise about 23% of VHL kindreds.[24] A new variant is by definition a postzygotic event, because it is not transmitted from a parent.

Depending on the embryogenesis stage at which the new variant occurs, there may be different somatic cell lineages carrying the variant; this influences the extent of mosaicism. Mosaicism is the presence in an individual of two or more cell lines that differ in genotype but which arise from a single zygote.[25] If the postzygotic de novo variant affects the gonadal cell line, there is a risk of transmitting a germline variant to offspring.[24]

VHL-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or pathogenic variants in VHL in which affected individuals develop abnormally high numbers of red blood cells. The affected individuals have biallelic pathogenic variants in the VHL gene. The typical VHL syndromic tumors do not occur in these affected individuals.[26-28]

In sporadic RCC, other genetic lesions have been found. These include PBRM1, SETD2, and BAP1 and may have relevance in RCC arising in VHL patients. Future studies will define their significance in the hereditary patient population.[29]

The VHL gene product, pVHL, is a 213 amino acid protein that regulates hypoxia-inducible factors (HIFs), maintains a normal extracellular matrix, is involved in microtubule and centrosome regulation, and regulates the cell cycle.[30-32] These functions are described in more detail in the following paragraphs.

pVHL regulates protein levels of HIF1-alpha and HIF2-alpha in the cell by acting as an E3 ubiquitin ligase for HIF. In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome.

Under hypoxic conditions, hydroxylation does not occur; HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex and are not ubiquitinated. The resulting high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of proteins. Loss of functional pVHL creates a pseudohypoxic state, with uncontrolled HIF1-alpha and HIF2-alpha protein levels, and resultant inappropriate transcription of HIF-dependent genes.

HIF1-alpha and HIF2-alpha possess distinct functional characteristics, and a shift towards a HIF2-alphadominant phenotype occurs in RCC. HIF1-alpha and HIF2-alpha may preferentially upregulate Myc activity.[33] Hypoxia activated factor has been shown to increase HIF2-alpha transactivation [34] and HIF1-alpha instability.[35] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha.[36]

Emerging data point to the importance of pVHL-mediated control of the primary cilium and the cilia centrosome cycle. The nonmotile primary cilium acts as a mechanosensor, is a regulator of cell signaling, and controls cellular entry into mitosis.[37] Loss of primary ciliary function results in the loss of the cells ability to maintain planar cell polarity, which results in cyst formation.[38] Loss of pVHL results in loss of the primary cilium.[39] pVHL binds to and stabilizes microtubules [40] in a glycogen synthase 3dependent fashion.[41] Loss of pVHL or expression of variant pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.[32]

pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[30] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[42] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[43] pVHL binds to, stabilizes, and transactivates p53 [44] in a phosphorylation-dependent fashion.[45] The importance of these findings is underscored by the findings that p53 is an important regulator of mitotic checkpoints, and loss of p53 permits aneuploid cells to survive.[46]

Functional pVHL is needed to form an extracellular fibronectin matrix.[47] Additionally, pVHL directly binds to, phosphorylates, and regulates fibronectin.[48] Collagen IV homeostasis is also regulated by pVHL. pVHL isoforms that are collagen IV bindingincompetent demonstrated a malignant phenotype.[31]

No representative VHL animal models are currently available. Vhlh gene knockout in mice did not produce RCC or hemangioblastomas.[49] Murine homologues of the R200W-induced polycythemia in mice, phenocopying Chuvash polycythemia.[50] A R167Q homologue did not generate RCC.[51] Coordinate inactivation of Vhlh and Pten resulted in a higher rate of cyst formation, but, once again, no obvious RCC was observed.[52] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[53] SETD2,[54] and BAP1 [55] provide new avenues for developing relevant animal models of at least some VHL disease manifestations.

The age at onset of VHL varies both from family to family and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. The youngest age at onset of specific VHL syndrome components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. At least one study has demonstrated that the incidence of new lesions varies depending on patient age, the underlying pathogenic variant, and the organ involved.[56] Examples of reported mean ages and age ranges of VHL clinical manifestations are summarized in Table 2.

(Refer to the Clinical diagnosis section of this summary for more information.)

Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[19] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[20] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[57] These specific VHL phenotypes are summarized below.

More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass.[58] Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2 or 4) and minimally invasive,[59] and their rate of growth varies widely.[60] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a cyst to a solid lesion was rare.[58] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.

Enlarge

Figure 1. von Hippel-Lindau syndromeassociated renal cell cancers are characteristically multifocal and bilateral and present as a combined cystic and solid mass. Red arrow indicates a lesion with a solid and cystic component, and white arrow indicates a predominantly solid lesion.

Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[60,61] RCCs often remain asymptomatic for long intervals.

Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[2] Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas).[62] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[63]

Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[64] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 35.9 years.[65] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children younger than 10 years.[65,66]

Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[64] The median number of lesions per affected eye is approximately six.[67] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[68]

Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [64] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[69] Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[67,70]

Hemangioblastomas are the most common disease manifestation in patients with VHL, potentially affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[71] After a mean follow-up of 7 years, 75% of the 225 patients studied developed new lesions. Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P < .01). Partial germline deletions were associated with more tumors per patient than were missense variants (P < .01). Younger patients developed more tumors per year. Hemangioblastoma growth rate was higher in men than in women (P < .01). Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.

Enlarge

Figure 2. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau syndrome. The left panel shows a sagittal view of brainstem and cerebellar lesions. The middle panel shows an axial view of a brainstem lesion. The right panel shows a cerebellar lesion (red arrow) with a dominant cystic component (white arrow).

Enlarge

Figure 3. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau syndrome. Multiple spinal cord hemangioblastomas are shown.

The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%,[72,73] with bilaterality occurring in some patients. Of patients with VHL pheochromocytomas, 44% developed disease in both adrenal glands.[74] One study reported a mean age at onset for pheochromocytoma in VHL patients of 30 years.[2] Rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL disease,[75] and approximately two-thirds will experience physical manifestations.[72] Missense VHL gene pathogenic variants correlated with the risk of pheochromocytoma in patients with VHL,[72] with a low incidence of pheochromocytoma in patients with complete deletion of the VHL gene. The rate of VHL germline pathogenic variants in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL disease.[76]

Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[77] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[74]

The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[73,78] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 years; P < .001).[78] Diagnosis of pheochromocytoma was made in patients as young as 5 years in one cohort,[73] providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.[73]

ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[79] ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[79,80] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[79,81]

ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[79,80] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[80] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[79]

Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[82,83] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[80,82]

Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[84] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[85] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[86] Therefore, any female with a broad ligament papillary cystadenoma should be referred for genetic counseling. These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.

More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL disease.[87] Among symptomatic patients, the most common presentation is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[88]

One group of investigators observed that epididymal tumorigenesis in VHL disease occurred in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells caused by developmental arrest of progenitor cells, followed by neoplastic papillary proliferation with activation/up-regulation of HIF and VEGF, associated with continuous reactive fibrovascular proliferation.[89] In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. CAIX was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[85]

The primary risk factor for VHL (or any of the hereditary forms of renal cancer under consideration) is the presence of a family member affected with the disease. Risk assessment should also consider gender and age for some specific VHL-related neoplasms. For example, pheochromocytomas may have onset in early childhood,[1] as early as 8 years of age.[90] Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%26%), which are virtually pathognomonic for VHL, especially when bilateral, and are rare in the general male population. Epididymal cysts are also common in VHL, but they are reported in 23% of the general male population, making them a poor diagnostic discriminator.[1] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[1]

Each offspring of an individual with VHL has a 50% chance of inheriting the VHL variant allele from their affected parent. Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, then a patient with one or more specific VHL-type tumors (e.g., hemangioblastoma of the CNS or retina, pheochromocytoma, or ccRCC) may be diagnosed with VHL.

At-risk family members should be informed that genetic testing for VHL is available. A family member with a clinical diagnosis of VHL or who is showing signs and symptoms of VHL is initially offered genetic testing. Germline pathogenic variants in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point variants in the VHL gene (~72% of all pathogenic variants).[91] Using Southern blot analysis and/or quantitative polymerase chain reaction to detect partial or complete gene deletions will detect pathogenic variants in the remaining 28% of VHL families.[91,92] The technique has a detection rate approaching 100%.[91] Newer techniques such as array comparative genomic hybridization (array CGH) are powerful tools for identifying genomic imbalances. Anecdotal evidence exists for the utility of next-generation sequencing in cases of suspected mosaicism with a negative VHL genetic test.[93]

Genetic counseling is first provided, including discussion of the medical, economic, and psychosocial implications for the patient and their bloodline relatives. After counseling, the patient may choose to voluntarily undergo testing, after providing informed consent. Additional counseling is given at the time results are reported to the patient. When a VHL pathogenic variant is identified in a family member, their biologic relatives who then test negative for the same pathogenic variant are not carriers of the trait (i.e., they are true negatives) and are not predisposed to developing any VHL manifestations. Equally important, the children of true-negative family members are not as risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.[13]

A germline pathogenic variant in the VHL gene is considered a genetic diagnosis. It is expected to carry a predisposition to clinical VHL and confers a 50% risk among offspring to inherit the VHL pathogenic variant. Approximately 400 unique pathogenic variants in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the variant. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL pathogenic variant is identified, that specific pathogenic variant becomes the DNA marker for which other biological relatives may be tested. In cases where there is a clear VHL clinical diagnosis without a VHL pathogenic variant by usual testing of peripheral blood lymphocytes and without a history of VHL in the biological parents or in the parents kindreds, then either a de novo pathogenic variant or mosaicism may be the cause. The latter may be detected by performing genetic testing on other bodily tissues, such as skin fibroblasts or exfoliated buccal cells.

Diagnosis of VHL is frequently based on clinical criteria (see Table 4). If there is family history of VHL, then a previously unevaluated family member may be diagnosed clinically if they present with one or more specific VHL-related tumors (e.g., CNS or retinal hemangioblastoma, pheochromocytoma, ccRCC, or endolymphatic sac tumor). If there is no family history of VHL, then a clinical diagnosis requires that the patient have two or more CNS hemangioblastomas or one CNS hemangioblastoma and a visceral tumor or endolymphatic sac tumor. See Table 4 for more diagnostic details.[2,13,14]

Since 1998, when a cohort of 93 VHL families in whom all germline pathogenic variants were identified was reported, diagnoses have included a combined approach of clinical and genetic testing within families. The diagnostic strategy differs among individual family members. Table 4 summarizes a combined approach of genetic testing and clinical diagnosis.

Surveillance guidelines that have been suggested for various manifestations of VHL are summarized in Table 5. In general, these recommendations are based on expert opinion and consensus; most are not evidence-based. These modalities may be used for the initial clinical diagnostic testing and also for periodic surveillance of at-risk individuals for early detection of developing neoplasm. Periodic presymptomatic screening is advised for at-risk individuals. At-risk individuals are those testing positive for a VHL pathogenic variant and those individuals who choose not to be tested for a VHL pathogenic variant but have biologic relatives affected by VHL. The risk of inheriting the VHL predisposition in such persons may be as high as 50%.

Level of evidence: 5

The management of VHL has changed significantly as clinicians have learned how to best balance the risk of cancer dissemination while minimizing renal morbidity. Some of the initial surgical series focused on performing a bilateral radical nephrectomy for renal tumors followed by a renal transplantation.[94,95] Nephron-sparing surgery (NSS) for VHL was introduced in the 1980s after several groups demonstrated a low risk of cancer dissemination with a less-radical surgical approach.[96,97] In 1995, a large, multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC.[98] Because of multiple reports of excellent outcomes, when feasible, NSS is now considered the surgical standard of care. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. To avoid the taking of a wide margin, enucleative resection was developed and allows the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.[99]

Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. To minimize the morbidity of multiple surgical procedures, loss of kidney function, and the risk of distant progression, a specific timing for intervention was questioned. The National Cancer Institute evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated before the largest lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[60] Later series reinforced that this was an important threshold because 0 of 108 patients with tumors managed at 3 cm or smaller had evidence of distant spread.[100] For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence.[100] This threshold is now widely used to trigger surgical intervention for VHL-associated ccRCC. When surgery is performed on a patient with VHL, resection of more than a dozen renal tumors may be necessary.[101] The use of intraoperative ultrasound to identify and then remove smaller lesions may delay the need for further surgical interventions.[102]

Many patients with VHL develop new RCCs on an ongoing basis and may require further intervention. Adhesions and perinephric scarring make subsequent surgical procedures more challenging. While a radical nephrectomy could be considered, NSS is still the preferred approach, when feasible. While there may be a higher incidence of complications, repeat and salvage NSS can enable patients to maintain excellent renal functional outcomes and provide promising oncologic outcomes at intermediate follow-up.[103,104] These surgeries may be best handled at a specialized center with significant experience with this surgical approach.[105]

Level of evidence: 3di

Thermal ablative techniques utilize either heating or cooling of a mass in an effort to destroy the tumor. Cryoablation (CA) and radiofrequency ablation (RFA) were introduced into the management of small renal masses in the late 1990s.[106,107] For sporadic renal masses, both thermal ablative techniques have a nearly 90% recurrence-free survival rate, leading the American Urologic Association to consider this as a recommendation in high-risk patients with a small renal mass.[108] For patients with VHL, the clinical applications of ablative techniques are still not clearly defined, and surgery is still the most-studied intervention. Ablative techniques were first introduced into the management of VHL-associated RCC in a phase II trial investigating the effects of ablation at the time of lesion resection. In this study, 11 tumors were treated, and an intra-operative ultrasound showed complete elimination of blood flow to the tumors; on final pathology, there was evidence of treatment effect on all tumors.[109] Since this time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success.[110] Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function.[111] Despite limited long-term data, these techniques have been increasingly utilized in the treatment of RCC in patients with VHL. A single-institution study evaluated treatment trends in RCC in 113 patients with VHL. Between 2004 and 2009, 43% of cases were managed with RFA at this center.[112]

Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. Cryoablation as salvage therapy was evaluated in a series of 14 patients to avoid the morbidity of repeat NSS. There was minimal change in renal function; at a median follow-up of 37 months, there was suspicion for lesion recurrence in only 4 of 33 tumors treated.[113] However, it must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications due to adhesions and scarring, especially along the tract of the ablative probes.[114-116] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[105,117]

The clinical applications of ablative techniques in VHL are still not clearly defined, and surgery is still the most-studied intervention. The available clinical evidence suggests that ablative approaches be reserved for small (3 cm), solid-enhancing renal masses in older patients with high operative risk, especially in patients facing salvage renal surgery because of a higher complication rate. Young age, tumor size larger than 4 cm, hilar tumors, and cystic lesions can be regarded as relative contraindications. Irreversible coagulopathy is widely accepted as an absolute contraindication.[118,119]

Level of evidence: 3di

A 2011 study prospectively evaluated the safety and efficacy of sunitinib in VHL patients.[120] Fifteen patients with VHL were given 50 mg of sunitinib daily for 28 days, followed by 14 days off for up to four cycles, with a primary endpoint of toxicity. Grade 3 toxicity included fatigue in five patients (33%); dose reductions were made in ten patients (75%). A significant response was observed in RCC but not in hemangioblastoma. Eighteen RCCs and 21 hemangioblastoma lesions were evaluable. Of these, six RCCs (33%) responded partially, versus none of the hemangioblastomas (P=.014). The expression of pFRS2 in hemangioblastoma tissue was also observed to be higher than in RCC, thus raising the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with hemangioblastoma.[120] A retrospective study of 14 patients with VHL, 10 of whom had metastatic disease, demonstrated significant response in metastatic and primary RCC lesions. Eleven patients had cerebellar hemangioblastomas, and eight had spinal hemangioblastomas. No response was seen in hemangioblastomas.[121]

Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[122-124] Modest improvement was observed in patients with retinal hemangioblastomas.[122,123] In a series of six VHL patients treated with SU5416, stabilization in CNS hemangioblastomas was observed in two patients.[124] A study of intravitreally administered antivascular endothelial growth factor therapy for a patient with retinal hemangioma yielded mixed results.[125] SU5416 is not licensed for human use.

Level of evidence: 2

Two studies suggest that pregnancy is associated with hemangioblastoma progression in patients with VHL.[126,127] One study retrospectively examined the records of 29 patients with VHL from the Netherlands who became pregnant 48 times (49 newborns) between 1966 and 2010 (40% became pregnant before 1990); imaging records were available for 31% of the pregnancies. Researchers reported that 17% of all pregnancies had VHL-related complications, including three patients who had craniospinal hemangioblastoma that significantly (P = .049) changed in progression score before and after pregnancy.[126] This study's findings are in contrast with a small, prospective investigation.[127] Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.

Morbidity and mortality in VHL vary and are influenced by the individual and the familys VHL phenotype (e.g., Type 1, 2A, 2B, or 2C). (Refer to the VHL familial phenotypes section of this summary for more information.)

In the past, metastatic RCC has caused about one-third of deaths in patients with VHL, and in some reports, it was the leading cause of death.[90,128-130] With increased surveillance of pathogenic variantpositive individuals, the RCC mortality rate is thought to have diminished.

Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem.[2] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[128,131] Hearing and vision may also be decreased or lost as a result of VHL tumors. Periodic screening allows early detection and may prevent advanced disease.

Currently, the renal manifestations of VHL are still generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies. These will include defining the molecular biology and genetics of kidney cancer development, which may result in the development of effective prevention or early intervention therapies. In addition, the evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHL function, identifying new targets, or discovering synthetic lethal strategies that can effectively eradicate RCC.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and RCC. Germline pathogenic variants in the fumarate hydratase (FH) gene are responsible for the susceptibility to HLRCC. FH encodes fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle).

Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern.[132] That report also described a woman aged 20 years with uterine leiomyosarcoma and metastatic RCC. Subsequently, the association of cutaneous and uterine leiomyomas became known as Reed syndrome. However, the clear association of cutaneous leiomyomas and RCC was not described until 2001, when a study reported two Finnish families in whom cutaneous and uterine leiomyomas and papillary type 2 RCC co-segregated.[3] The name hereditary leiomyomatosis and renal cell cancer was then assigned. The term HLRCC is preferred because it is impossible to distinguish between individuals with cutaneous leiomyomas who do or do not have an increased risk of renal cancer.

The FH gene consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. The human FH gene is located on chromosome 1q42.3-43.

HLRCC is an autosomal dominant syndrome; a single variant FH allele is sufficient to cause the disease.[133] Inherited biallelic pathogenic variants cause fumarate hydratase deficiency (FHD), a disorder characterized by rapidly progressive neonatal neurologic impairment including hypotonia, seizures, and cerebral atrophy. (Refer to the Genetically related disorders section of this summary for more information.)

Germline pathogenic variants in FH, plus somatic variants and loss of heterozygosity (LOH) in RCC, suggest that loss of function in the fumarate hydratase protein is the basis of tumor formation in HLRCC and, further, that FH functions as a tumor suppressor gene.[3,134]

Various pathogenic variants in FH have been identified in families with HLRCC. Most are missense pathogenic variants, but nonsense, frameshift, and splice-site variants have been described.[5,6,134,135] Recently, whole-gene or partial deletions have been identified.

The prevalence of HLRCC is unknown. It is estimated that more than 100 families with HLRCC have been seen at the National Institutes of Health, but it is likely that HLRCC remains an underrecognized entity (R. Srinivasan, MD, PhD, oral communication, April 2014).

Considering the three major clinical manifestations combined, the penetrance of HLRCC is considered to be very high. However, the estimated cumulative incidence of RCC varies widely, from between 2% and 7% to 15%, and perhaps as high as 32%, in families with germline FH pathogenic variants, depending on ascertainment method and the imaging modalities used.[3-6,136]

No genotype-phenotype correlations have been described. Thus, no correlation has been observed between specific FH variants and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.[6]

Although smaller studies have suggested the presence of different variant spectra in FHD and HLRCC,[5,134] a study that included a larger cohort of patients indicated that the variant distribution is fairly similar in these two entities.[133] The predisposition to HLRCC versus FHD likely results from a difference in gene dosage, rather than the location of the FH variant as originally suggested.[134]

Between 80% and 100% of individuals with HLRCC have identifiable, deleterious sequence alterations in FH.[5,6,137]

FHD, resulting from the inheritance of biallelic pathogenic variants in FH, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline pathogenic variants in FH are found in individuals with FHD.[138,139] To date, RCC has not been reported in FHD-affected individuals. Most individuals with FHD survive only a few months; very few survive to early adulthood.[140] However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.[134]

LOH around the FH locus has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumor characteristics of the heritable disease.[141,142] All three tumors displayed biallelic inactivation of FH. In sporadic forms of kidney cancer, there have been no somatic pathogenic variants identified in FH to date.[141]

The mechanisms by which alterations in FH lead to HLRCC are still being elucidated. Biallelic inactivation of FH has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Blockage of the Krebs cycle at FH results in increased levels of intracellular fumarate, inhibiting HIF prolyl hydroxylases. Inactivating variants of FH also appear to result in the generation of reactive oxygen species, further contributing to the stabilization of HIF.[143] This upregulation of the HIF pathway leads to a pseudohypoxic state and upregulation of a transcriptional program contributing to aggressive tumor biology.[144] Others have demonstrated upregulation of the antioxidant response pathway due to posttranslational modification of KEAP1. The resultant NRF-2 dysregulation leads to upregulation of antioxidant response elementcontrolled genes such as aldo-keto reductase family 1 member, B10 (AKR1B10), possibly contributing to the neoplastic process.[145]

The clinical characteristics of HLRCC include cutaneous leiomyomas, uterine leiomyomas (fibroids), and RCC. Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; an RCC that is typically solitary, or no renal tumors; and/or uterine leiomyomas. Disease severity shows significant intrafamilial and interfamilial variation.[3,5,6]

Cutaneous leiomyomas present as firm pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 1047 years) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful. Pain is correlated with severity of cutaneous involvement.[5] The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup; a solitary leiomyoma requires careful analysis of family history. (Refer to the Clinical diagnosis and Differential diagnosis sections below for more information.)

The onset of uterine leiomyomas in women with HLRCC occurs at a younger age than in women in the general population. The age at diagnosis ranges from 18 to 52 years (mean age, 30 years). Uterine leiomyomas are usually large and numerous. Most women experience symptoms including irregular or heavy menstruation and pelvic pain, thus requiring treatment at a younger age than females with leiomyomas in the general population. Women with HLRCC and uterine leiomyomas undergo hysterectomy or myomectomy for symptomatic uterine leiomyomas at a younger age (<30 years) than do women in the general population (median age, 45 years).[5,137,146,147]

The symptoms of RCC may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with RCC are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop RCC. Most RCCs are unilateral and solitary; in a few individuals, they are multifocal. Approximately 10% to 32% of individuals with HLRCC who presented with multiple cutaneous leiomyomas had RCC at the time that renal imaging was performed.[5,137] The median age at detection of RCC was 37 years,[148] although some cases have been reported to occur as early as age 10 years.[149] In contrast to other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[150,151] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.[5] Figure 4 depicts RCCs in a patient with HLRCC.

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Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ)Health ...

This article is about the general scientific term. For the scientific journal, see Genetics (journal).

Genetics is the study of genes, genetic variation, and heredity in living organisms.[1][2] It is generally considered a field of biology, but it intersects frequently with many of the life sciences and is strongly linked with the study of information systems.

The father of genetics is Gregor Mendel, a late 19th-century scientist and Augustinian friar. Mendel studied 'trait inheritance', patterns in the way traits were handed down from parents to offspring. He observed that organisms (pea plants) inherit traits by way of discrete "units of inheritance". This term, still used today, is a somewhat ambiguous definition of what is referred to as a gene.

Trait inheritance and molecular inheritance mechanisms of genes are still primary principles of genetics in the 21st century, but modern genetics has expanded beyond inheritance to studying the function and behavior of genes. Gene structure and function, variation, and distribution are studied within the context of the cell, the organism (e.g. dominance) and within the context of a population. Genetics has given rise to a number of sub-fields including epigenetics and population genetics. Organisms studied within the broad field span the domain of life, including bacteria, plants, animals, and humans.

Genetic processes work in combination with an organism's environment and experiences to influence development and behavior, often referred to as nature versus nurture. The intra- or extra-cellular environment of a cell or organism may switch gene transcription on or off. A classic example is two seeds of genetically identical corn, one placed in a temperate climate and one in an arid climate. While the average height of the two corn stalks may be genetically determined to be equal, the one in the arid climate only grows to half the height of the one in the temperate climate due to lack of water and nutrients in its environment.

The word genetics stems from the Ancient Greek genetikos meaning "genitive"/"generative", which in turn derives from genesis meaning "origin".[3][4][5]

The observation that living things inherit traits from their parents has been used since prehistoric times to improve crop plants and animals through selective breeding.[6] The modern science of genetics, seeking to understand this process, began with the work of Gregor Mendel in the mid-19th century.[7]

Prior to Mendel, Imre Festetics, a Hungarian noble, who lived in Kszeg before Mendel, was the first who used the word "genetics". He described several rules of genetic inheritance in his work The genetic law of the Nature (Die genetische Gestze der Natur, 1819). His second law is the same as what Mendel published. In his third law, he developed the basic principles of mutation (he can be considered a forerunner of Hugo de Vries.)[8]

Other theories of inheritance preceded his work. A popular theory during Mendel's time was the concept of blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents.[9] Mendel's work provided examples where traits were definitely not blended after hybridization, showing that traits are produced by combinations of distinct genes rather than a continuous blend. Blending of traits in the progeny is now explained by the action of multiple genes with quantitative effects. Another theory that had some support at that time was the inheritance of acquired characteristics: the belief that individuals inherit traits strengthened by their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrongthe experiences of individuals do not affect the genes they pass to their children,[10] although evidence in the field of epigenetics has revived some aspects of Lamarck's theory.[11] Other theories included the pangenesis of Charles Darwin (which had both acquired and inherited aspects) and Francis Galton's reformulation of pangenesis as both particulate and inherited.[12]

Modern genetics started with Gregor Johann Mendel, a scientist and Augustinian friar who studied the nature of inheritance in plants. In his paper "Versuche ber Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brnn, Mendel traced the inheritance patterns of certain traits in pea plants and described them mathematically.[13] Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work did not gain wide understanding until the 1890s, after his death, when other scientists working on similar problems re-discovered his research. William Bateson, a proponent of Mendel's work, coined the word genetics in 1905.[14][15] (The adjective genetic, derived from the Greek word genesis, "origin", predates the noun and was first used in a biological sense in 1860.)[16] Bateson both acted as a mentor and was aided significantly by the work of women scientists from Newnham College at Cambridge, specifically the work of Becky Saunders, Nora Darwin Barlow, and Muriel Wheldale Onslow.[17] Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.[18]

After the rediscovery of Mendel's work, scientists tried to determine which molecules in the cell were responsible for inheritance. In 1911, Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies.[19] In 1913, his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome.[20]

Although genes were known to exist on chromosomes, chromosomes are composed of both protein and DNA, and scientists did not know which of the two is responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, the AveryMacLeodMcCarty experiment identified DNA as the molecule responsible for transformation.[21] The role of the nucleus as the repository of genetic information in eukaryotes had been established by Hmmerling in 1943 in his work on the single celled alga Acetabularia.[22] The HersheyChase experiment in 1952 confirmed that DNA (rather than protein) is the genetic material of the viruses that infect bacteria, providing further evidence that DNA is the molecule responsible for inheritance.[23]

James Watson and Francis Crick determined the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin and Maurice Wilkins that indicated DNA had a helical structure (i.e., shaped like a corkscrew).[24][25] Their double-helix model had two strands of DNA with the nucleotides pointing inward, each matching a complementary nucleotide on the other strand to form what looks like rungs on a twisted ladder.[26] This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for replication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand. This property is what gives DNA its semi-conservative nature where one strand of new DNA is from an original parent strand.[27]

Although the structure of DNA showed how inheritance works, it was still not known how DNA influences the behavior of cells. In the following years, scientists tried to understand how DNA controls the process of protein production.[28] It was discovered that the cell uses DNA as a template to create matching messenger RNA, molecules with nucleotides very similar to DNA. The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein; this translation between nucleotide sequences and amino acid sequences is known as the genetic code.[29]

With the newfound molecular understanding of inheritance came an explosion of research.[30] A notable theory arose from Tomoko Ohta in 1973 with her amendment to the neutral theory of molecular evolution through publishing the nearly neutral theory of molecular evolution. In this theory, Ohta stressed the importance of natural selection and the environment to the rate at which genetic evolution occurs.[31] One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger. This technology allows scientists to read the nucleotide sequence of a DNA molecule.[32] In 1983, Kary Banks Mullis developed the polymerase chain reaction, providing a quick way to isolate and amplify a specific section of DNA from a mixture.[33] The efforts of the Human Genome Project, Department of Energy, NIH, and parallel private efforts by Celera Genomics led to the sequencing of the human genome in 2003.[34]

At its most fundamental level, inheritance in organisms occurs by passing discrete heritable units, called genes, from parents to progeny.[35] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.[13][36] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or whitebut never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of the pea, which is a diploid species, each individual plant has two copies of each gene, one copy inherited from each parent.[37] Many species, including humans, have this pattern of inheritance. Diploid organisms with two copies of the same allele of a given gene are called homozygous at that gene locus, while organisms with two different alleles of a given gene are called heterozygous.

The set of alleles for a given organism is called its genotype, while the observable traits of the organism are called its phenotype. When organisms are heterozygous at a gene, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.[38]

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

Geneticists use diagrams and symbols to describe inheritance. A gene is represented by one or a few letters. Often a "+" symbol is used to mark the usual, non-mutant allele for a gene.[39]

In fertilization and breeding experiments (and especially when discussing Mendel's laws) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.

When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits.[40] These charts map the inheritance of a trait in a family tree.

Organisms have thousands of genes, and in sexually reproducing organisms these genes generally assort independently of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all or are white. When a plant has two copies of this white allele, its flowers are whiteregardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.[41]

Many traits are not discrete features (e.g. purple or white flowers) but are instead continuous features (e.g. human height and skin color). These complex traits are products of many genes.[42] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability.[43] Measurement of the heritability of a trait is relativein a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a trait with complex causes. It has a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.[44]

The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain.[45]Viruses are the only exception to this rulesometimes viruses use the very similar molecule, RNA, instead of DNA as their genetic material.[46] Viruses cannot reproduce without a host and are unaffected by many genetic processes, so tend not to be considered living organisms.

DNA normally exists as a double-stranded molecule, coiled into the shape of a double helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.[47]

Genes are arranged linearly along long chains of DNA base-pair sequences. In bacteria, each cell usually contains a single circular genophore, while eukaryotic organisms (such as plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length.[48] The DNA of a chromosome is associated with structural proteins that organize, compact and control access to the DNA, forming a material called chromatin; in eukaryotes, chromatin is usually composed of nucleosomes, segments of DNA wound around cores of histone proteins.[49] The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.

While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene.[37] The two alleles for a gene are located on identical loci of the two homologous chromosomes, each allele inherited from a different parent.

Many species have so-called sex chromosomes that determine the gender of each organism.[50] In humans and many other animals, the Y chromosome contains the gene that triggers the development of the specifically male characteristics. In evolution, this chromosome has lost most of its content and also most of its genes, while the X chromosome is similar to the other chromosomes and contains many genes. The X and Y chromosomes form a strongly heterogeneous pair.

When cells divide, their full genome is copied and each daughter cell inherits one copy. This process, called mitosis, is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.

Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction alternates between forms that contain single copies of the genome (haploid) and double copies (diploid).[37] Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes such as sperm or eggs.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium.[51] Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genomes, a phenomenon known as transformation.[52] These processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would be otherwise unrelated.

The diploid nature of chromosomes allows for genes on different chromosomes to assort independently or be separated from their homologous pair during sexual reproduction wherein haploid gametes are formed. In this way new combinations of genes can occur in the offspring of a mating pair. Genes on the same chromosome would theoretically never recombine. However, they do via the cellular process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes.[53] This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid cells.

The first cytological demonstration of crossing over was performed by Harriet Creighton and Barbara McClintock in 1931. Their research and experiments on corn provided cytological evidence for the genetic theory that linked genes on paired chromosomes do in fact exchange places from one homolog to the other.

The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between the points. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated.[54] For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage; alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.[55]

Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are made up of one or more polypeptide chains, each of which is composed of a sequence of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific amino acid sequence. This process begins with the production of an RNA molecule with a sequence matching the gene's DNA sequence, a process called transcription.

This messenger RNA molecule is then used to produce a corresponding amino acid sequence through a process called translation. Each group of three nucleotides in the sequence, called a codon, corresponds either to one of the twenty possible amino acids in a protein or an instruction to end the amino acid sequence; this correspondence is called the genetic code.[56] The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but it never transfers from protein back into the sequence of DNAa phenomenon Francis Crick called the central dogma of molecular biology.[57]

The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of proteins are related to their functions.[58][59] Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.

A single nucleotide difference within DNA can cause a change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the -globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties.[60] Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clog or degrade, causing the medical problems associated with this disease.

Some DNA sequences are transcribed into RNA but are not translated into protein productssuch RNA molecules are called non-coding RNA. In some cases, these products fold into structures which are involved in critical cell functions (e.g. ribosomal RNA and transfer RNA). RNA can also have regulatory effects through hybridization interactions with other RNA molecules (e.g. microRNA).

Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotypes an organism displays. This is the complementary relationship often referred to as "nature and nurture". The phenotype of an organism depends on the interaction of genes and the environment. An interesting example is the coat coloration of the Siamese cat. In this case, the body temperature of the cat plays the role of the environment. The cat's genes code for dark hair, thus the hair-producing cells in the cat make cellular proteins resulting in dark hair. But these dark hair-producing proteins are sensitive to temperature (i.e. have a mutation causing temperature-sensitivity) and denature in higher-temperature environments, failing to produce dark-hair pigment in areas where the cat has a higher body temperature. In a low-temperature environment, however, the protein's structure is stable and produces dark-hair pigment normally. The protein remains functional in areas of skin that are colder such as its legs, ears, tail and face so the cat has dark-hair at its extremities.[61]

Environment plays a major role in effects of the human genetic disease phenylketonuria.[62] The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive mental retardation and seizures. However, if someone with the phenylketonuria mutation follows a strict diet that avoids this amino acid, they remain normal and healthy.

A popular method for determining how genes and environment ("nature and nurture") contribute to a phenotype involves studying identical and fraternal twins, or other siblings of multiple births.[63] Because identical siblings come from the same zygote, they are genetically the same. Fraternal twins are as genetically different from one another as normal siblings. By comparing how often a certain disorder occurs in a pair of identical twins to how often it occurs in a pair of fraternal twins, scientists can determine whether that disorder is caused by genetic or postnatal environmental factors whether it has "nature" or "nurture" causes. One famous example is the multiple birth study of the Genain quadruplets, who were identical quadruplets all diagnosed with schizophrenia.[64] However such tests cannot separate genetic factors from environmental factors affecting fetal development.

The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to DNA, either promoting or inhibiting the transcription of a gene.[65] Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genestryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process.[66]

Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into variant cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. As no single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.

Within eukaryotes, there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells.[67] These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.[68]

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low1 error in every 10100million basesdue to the "proofreading" ability of DNA polymerases.[69][70] Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure.[71] Chemical damage to DNA occurs naturally as well and cells use DNA repair mechanisms to repair mismatches and breaks. The repair does not, however, always restore the original sequence.

In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations.[72] Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence duplications, inversions, deletions of entire regions or the accidental exchange of whole parts of sequences between different chromosomes (chromosomal translocation).

Mutations alter an organism's genotype and occasionally this causes different phenotypes to appear. Most mutations have little effect on an organism's phenotype, health, or reproductive fitness.[73] Mutations that do have an effect are usually deleterious, but occasionally some can be beneficial.[74] Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, about 70 percent of these mutations will be harmful with the remainder being either neutral or weakly beneficial.[75]

Population genetics studies the distribution of genetic differences within populations and how these distributions change over time.[76] Changes in the frequency of an allele in a population are mainly influenced by natural selection, where a given allele provides a selective or reproductive advantage to the organism,[77] as well as other factors such as mutation, genetic drift, genetic draft,[78]artificial selection and migration.[79]

Over many generations, the genomes of organisms can change significantly, resulting in evolution. In the process called adaptation, selection for beneficial mutations can cause a species to evolve into forms better able to survive in their environment.[80] New species are formed through the process of speciation, often caused by geographical separations that prevent populations from exchanging genes with each other.[81] The application of genetic principles to the study of population biology and evolution is known as the "modern synthesis".

By comparing the homology between different species' genomes, it is possible to calculate the evolutionary distance between them and when they may have diverged. Genetic comparisons are generally considered a more accurate method of characterizing the relatedness between species than the comparison of phenotypic characteristics. The evolutionary distances between species can be used to form evolutionary trees; these trees represent the common descent and divergence of species over time, although they do not show the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria).[82]

Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research.[83] Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.

Organisms were chosen, in part, for convenienceshort generation times and easy genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).

Medical genetics seeks to understand how genetic variation relates to human health and disease.[84] When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a method especially useful for multigenic traits not clearly defined by a single gene.[85] Once a candidate gene is found, further research is often done on the corresponding gene the orthologous gene in model organisms. In addition to studying genetic diseases, the increased availability of genotyping methods has led to the field of pharmacogenetics: the study of how genotype can affect drug responses.[86]

Individuals differ in their inherited tendency to develop cancer,[87] and cancer is a genetic disease.[88] The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide. Although these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process; signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.

Normally, a cell divides only in response to signals called growth factors and stops growing once in contact with surrounding cells and in response to growth-inhibitory signals. It usually then divides a limited number of times and dies, staying within the epithelium where it is unable to migrate to other organs. To become a cancer cell, a cell has to accumulate mutations in a number of genes (37) that allow it to bypass this regulation: it no longer needs growth factors to divide, it continues growing when making contact to neighbor cells, and ignores inhibitory signals, it will keep growing indefinitely and is immortal, it will escape from the epithelium and ultimately may be able to escape from the primary tumor, cross the endothelium of a blood vessel, be transported by the bloodstream and will colonize a new organ, forming deadly metastasis. Although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations that originally appear and accumulate in one or a small number of cells that will divide to form the tumor and are not transmitted to the progeny (somatic mutations). The most frequent mutations are a loss of function of p53 protein, a tumor suppressor, or in the p53 pathway, and gain of function mutations in the ras proteins, or in other oncogenes.

DNA can be manipulated in the laboratory. Restriction enzymes are commonly used enzymes that cut DNA at specific sequences, producing predictable fragments of DNA.[89] DNA fragments can be visualized through use of gel electrophoresis, which separates fragments according to their length.

The use of ligation enzymes allows DNA fragments to be connected. By binding ("ligating") fragments of DNA together from different sources, researchers can create recombinant DNA, the DNA often associated with genetically modified organisms. Recombinant DNA is commonly used in the context of plasmids: short circular DNA molecules with a few genes on them. In the process known as molecular cloning, researchers can amplify the DNA fragments by inserting plasmids into bacteria and then culturing them on plates of agar (to isolate clones of bacteria cells). ("Cloning" can also refer to the various means of creating cloned ("clonal") organisms.)

DNA can also be amplified using a procedure called the polymerase chain reaction (PCR).[90] By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.

DNA sequencing, one of the most fundamental technologies developed to study genetics, allows researchers to determine the sequence of nucleotides in DNA fragments. The technique of chain-termination sequencing, developed in 1977 by a team led by Frederick Sanger, is still routinely used to sequence DNA fragments.[91] Using this technology, researchers have been able to study the molecular sequences associated with many human diseases.

As sequencing has become less expensive, researchers have sequenced the genomes of many organisms, using a process called genome assembly, which utilizes computational tools to stitch together sequences from many different fragments.[92] These technologies were used to sequence the human genome in the Human Genome Project completed in 2003.[34] New high-throughput sequencing technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars.[93]

Next generation sequencing (or high-throughput sequencing) came about due to the ever-increasing demand for low-cost sequencing. These sequencing technologies allow the production of potentially millions of sequences concurrently.[94][95] The large amount of sequence data available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data. A common problem to these fields of research is how to manage and share data that deals with human subject and personally identifiable information. See also genomics data sharing.

On 19 March 2015, a leading group of biologists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited.[96][97][98][99] In April 2015, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[100][101]

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Genetics - Wikipedia

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The public health burden of prostate cancer is substantial. A total of 180,890 new cases of prostate cancer and 26,120 deaths from the disease are anticipated in the United States in 2016, making it the most frequent nondermatologic cancer among U.S. males.[1] A mans lifetime risk of prostate cancer is one in seven. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patients life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate than white men.[4] African American men have been reported to have more than twice the rate of prostate cancerspecific death compared with non-Hispanic white men.[1] Differences in race-specific prostate cancer survival estimates may be narrowing over time.[5]

These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[6] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[7] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, and there is increasing knowledge of the molecular genetics of the disease, although much of what is known is not yet clinically actionable. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[8]

The three most important recognized risk factors for prostate cancer in the United States are:

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 325 for men 49 years or younger, 1 in 48 for men aged 50 through 59 years, 1 in 17 for men aged 60 through 69 years, and 1 in 10 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]

Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer is increasing, and there is evidence that some cases may be more aggressive.[9] Because early-onset cancers may result from germline mutations, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[10,11] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[12]

Prostate cancer is highly heritable; the inherited risk of prostate cancer has been estimated to be as high as 60%.[13] As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[14-18] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[15,19,20] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[16-20] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[21]

Although some of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[22-24] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)[25]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[26] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.052.20) with an affected father only, 2.96 (95% CI, 2.803.13) with an affected brother only, and 8.51 (95% CI, 6.1311.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.2625.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[27] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR, 1.7; 95% CI, 1.03.0; multivariate RR, 1.7; 95% CI, 0.93.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR, 5.8; 95% CI, 2.414.0).[22] Analysis of data from the Women's Health Initiative also showed that a family history of prostate cancer was associated with an increase in the risk of postmenopausal breast cancer (adjusted HR, 1.14; 95% CI, 1.021.26).[28] Further analyses showed that breast cancer risk was associated with a family history of both breast and prostate cancers; the risk was higher in black women than in white women. Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[22,29] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[30] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[31-34] (Refer to the BRCA1 and BRCA2 section of this summary for more information.)

Prostate cancer clusters with particular intensity in some families. Highly penetrant genetic variants are thought to be associated with prostate cancer risk in these families. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age at diagnosis and specific family cancer history patterns.[35,36] Individuals meeting the following criteria may warrant referral for genetic consultation:[35-38]

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[39] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.93.3) with adjustment for age and ethnicity.[39]

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone before puberty do not develop prostate cancer.[40] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[41] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[42] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[43]

(Refer to the PDQ summary on Prostate Cancer Prevention for more information about nongenetic modifiers of prostate cancer risk in the general population.)

The SEER Cancer Registries assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.015.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed before age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus; and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[44]

A review of more than 441,000 men diagnosed with prostate cancer between 1992 and 2010 demonstrated similar findings, with an overall reduction in the risk of being diagnosed with a second primary cancer. This study also examined the risk of second primary cancers in 44,310 men (10%) by treatment modality for localized cancer. The study suggested that men who received radiation therapy had increases in bladder (standardized incidence ratio [SIR], 1.42) and rectal cancer risk (SIR, 1.70) compared with those who did not receive radiation therapy (SIRbladder, 0.76; SIRrectal, 0.74).[45]

The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors, including treatment modality. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[44]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the RR was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[46]

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[47-49]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (SIR, 1.9; 95% CI, 1.03.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer sitespecific disorder.[50]

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic (MZ) and dizygotic (DZ) twin pairs in Scandinavia concluded that 58% (95% CI, 5263) of prostate cancer risk may be accounted for by heritable factors.[13] Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins (mean, 3.8 years in MZ twins vs. 6.5 years in DZ twins). This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs.[51] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[15] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[52]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[53-55] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[51] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [56-59] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (<66 years) than noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[60]

Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, are moderately to highly penetrant in families, and have large (e.g., relative risk >2.0) effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have low to modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a mans lifetime risk of prostate cancer is one in seven,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. There are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease, although current advances in the understanding of molecular phenotypes of prostate cancer may be informative in identifying inherited prostate cancer. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score 7, PSA 20 ng/mL) in an affected man.[5-7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate canceraffected individuals. Conflicting evidence exists regarding the linkage to some of the loci described above. Data on the proposed phenotype associated with each locus are also limited, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (2) logarithm of the odds (LOD) score, heterogeneity LOD (HLOD) score, or summary LOD score:

The chromosomal region 19q has also been found to be associated with prostate cancer, although specific LOD scores have not been described.[8,11,95]

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint HLOD scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[92,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[111] Further study including a larger number of African American families is needed to confirm these findings.

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (HLOD score = 2.18) and 22q12.3-q13.1 (HLOD score = 1.90).[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[107] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[112] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.093.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.

In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[113] A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[114] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 hereditary prostate cancer families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[113]

Linkage to chromosome 17q21-22 and subsequent fine-mapping and targeted sequencing have identified recurrent mutations in the HOXB13 gene that account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. Multiple studies have confirmed the association between the G84E mutation in HOXB13 and prostate cancer risk. (Refer to the HOXB13 section of this summary for more information.) The clinical utility of testing for HOXB13 mutations has not yet been defined, but studies are ongoing to define the clinical role. For example, a study evaluated 948 unselected men scheduled for prostate biopsy. The G84E mutation was found in three men (0.3%) who had prostate cancer detected on biopsy, although none of the 301 men who had a family history of prostate cancer carried the mutation.[115] Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional moderately to highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.[116]

A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[117,118]

Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[117,118]

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[120] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[121]

Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[122,123] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[120,122-132] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.11.3) and short GGN length (OR, 1.3; 95% CI, 1.11.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[133] Subsequently, the large multiethnic cohort study of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[134] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.081.69; P = .03).[135]

An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Mens Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[136] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[134,137,138] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[139] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[140] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[141]

Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone (DHT) by 5-alpha-reductase type II.[142] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[143,144]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[145] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[142,146] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[120,142] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[147] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.012.08; OR, 1.49; 95% CI, 1.032.15).[135] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.092.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.142.68).[148] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[149]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.350.88; OR, 0.57; 95% CI, 0.360.90; OR, 0.55; 95% CI, 0.350.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.942.63).[150] Additional studies are needed to confirm these findings.

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[151] This study awaits replication.

Germline mutations in the tumor suppressor gene E-cadherin (also called CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene.[152] Because somatic mutations in E-cadherin have been implicated in the development of invasive malignancies in a number of different cancers,[153] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.111.60). However, the authors of the study noted that there are sources of bias in the dataset, stemming mostly from the small sample sizes of individual cohorts.[154] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[155] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[156] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[157-161] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[162] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.330.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[163] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[164] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < .001). In African Americans, SNPs within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1 showed a significant interaction (P = .014). In non-Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at three SNPs in HSD3B2 and CYP19 (OR, 2.20; 95% CI, 1.443.38; P = .0003). In Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at two SNPs in CYP19 and CYP24A1 (OR, 4.29; 95% CI, 2.118.72; P = .00006). While this study did not evaluate all potentially important SNPs in genes in the steroid hormone pathway, it demonstrates how studies can be performed to evaluate multigenic effects in multiple populations to assess the contribution to prostate cancer risk.

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[165]

Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[166] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[167] Therefore, the biologic basis of the various associations identified requires further study.

Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for hereditary prostate cancer susceptibility has not been established.

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[178] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[179,180]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[182] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[179] (Refer to the GWAS section of this summary for more information.)

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[183] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[184,185] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to scan the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million to 5 million SNPs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signalsin which allele frequencies deviate significantly in case compared to control populationsare validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently when standard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 10-7.[186-188]

To date, approximately 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4).[189] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[192]

In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70-73,80-83,193] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73-75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54128.62 Mb, region 2 at 128.14128.28 Mb, and region 3 (containing rs6983267) at 128.47128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]

Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[206] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are included in Table 5. The association between risk and allele status for each variant listed in Table 5 reached genome-wide statistical significance in more than one independent cohort.

The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[208] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.

Some of the risk variants identified in Table 5 have also been found to confer risk in men of European ancestry. These include rs16901979, rs6983267, and rs1447295 at 8q24 in African Americans and rs13254738 in Japanese populations. Additionally, the Japanese rs4430796 at 17q12 and rs2660753 at 3p12 have also been observed in men of European ancestry. However, the vast majority of the variants identified in these studies reveal novel variants that are unique to that specific ethnic population. These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.936.80; P = 1.20 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.6224.72; P = 1.29 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.646.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.835.33).[214]

However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[215] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[216]

Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[217]

In another study, 49 risk SNPs were genotyped in 2,696 Swedish men, and a polygenic risk score was calculated. On the basis of their genetic risk scores, 172 men aged 50 to 69 years with PSA levels of 1 to 3 ng/mL underwent biopsy. Prostate cancer was diagnosed in 27% of these individuals, and 6% had Gleason 7 or higher disease.[218] The utility of this strategy for identifying who should undergo prostate biopsy is yet to be determined.

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[216] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have poor discriminative ability to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional common risk alleles (alleles carried by >1%5% of individuals within the population).[219]

GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by <1% of the population). These variants were analyzed in 5,141 prostate cancer cases and 54,444 controls (genotypes were imputed in cases in which they had not been genotyped in previous analyses). In addition to previously reported risk alleles at 8q24 and 17q12, significant associations with prostate cancer were observed for two rare 8q24 SNPsthe minor allele (the G allele) of rs183373024 (OR, 2.69; P = 1.5 1023) and the minor allele (the A allele) of rs188140481 (OR, 2.88; P = 1.5 1022).[220] These results were validated in independent cohorts of European cases and controls. The frequencies of the risk alleles of these two variants in controls ranged from 0.1% to 1.1% and were lowest in southern Europe and highest in northern Europe. These data, in which risk alleles had high ORs compared with previous GWAS, demonstrate that the bulk of inherited risk may reside in rare alleles.

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.

Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:

The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[222] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[223-225] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[226] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[224,226] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.

Additional insights are emerging regarding the potential interaction between SNPs identified from GWAS and prostate cancer susceptibility gene regulation. One study found that a SNP at 6q22 lies within a binding region for HOXB13. Through multiple functional approaches, the T allele of this SNP (rs339331) was found to enhance binding of HOXB13, leading to allele-specific upregulation of RFX6, which correlates with prostate cancer progression and severity.[227] Thus, this study supports the hypothesis that risk alleles identified from GWAS may play a role in regulating or modifying gene expression and therefore impact prostate cancer risk.

A 2012 study used a novel approach to identify polymorphisms associated with risk.[228] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13a locus previously implicated in cancer developmentassociated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.131.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[229] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Prostate cancer is clinically heterogeneous. Many cases are indolent and are successfully managed with observation alone. Other cases are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed, as sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers since they are present, easily detectable, and static throughout life. Several studies have interrogated inherited variants that may distinguish indolent and aggressive prostate cancer. Several of these studies identified polymorphisms associated with aggressiveness, after adjusting for commonly used clinical variables, and are reviewed in the Table 6.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess prospectively.

Like studies of the genetics of prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes. Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain risk SNPs were also associated with aggressiveness (see table below). There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer. While GWAS designed explicitly for disease aggressiveness have been initiated, most genome-wide analyses to date have relied on datasets previously generated to evaluate prostate cancer risk. The cases from these case-control cohorts were divided into aggressive and nonaggressive subgroups then compared with each other and/or with the control (nonprostate cancer) subjects. Several associations between germline markers and prostate cancer aggressiveness have been reported. However, there remains no accepted set of germline markers that clearly provides prognostic information beyond that provided by more traditional variables at the time of diagnosis.

In independent retrospective series (see Table 6) the prostate cancer risk allele at rs2735839 (G) was associated with less aggressive disease. This risk allele has also been associated with higher PSA levels.[198,238] A hypothesis explaining the association between the nonrisk allele (A) and more aggressive disease is that those carrying the A allele generally have lower PSA levels and are sent for prostate biopsy less often. They subsequently may be diagnosed later in the natural history of the disease, resulting in poorer outcomes.

To definitively identify the inherited variants associated with prostate cancer aggressiveness, GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. Notably, in a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths), no SNP was associated with prostate cancerspecific survival.[239] The authors concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%). As more data regarding rarer variants are generated and validated, the value of inherited variants for therapeutic decision making may be determined.

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2] Prostate cancer in particular has been observed at higher rates in male BRCA2 mutations carriers than in the general population.[3]

The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 7.

Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[6] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[7-9] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.71.1) for the 185delAG mutation, 0.3% (95% confidence interval [CI], 0.20.4) for the 5382insC mutation, and 1.3% (95% CI, 1.01.5) for the BRCA2 6174delT mutation.[10-13] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks (RRs) were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 430) among carriers and 3.8% among noncarriers (95% CI, 3.34.4).[13] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 70 years; 95% CI, 628). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

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Genetics of Prostate Cancer (PDQ)Health Professional ...

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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Cell Size and Scale - Learn Genetics

Have you ever wondered how scientists work with tiny molecules that they can't see? Here's your chance to try it yourself! Sort and measure DNA strands by running your own gel electrophoresis experiment.

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APA format:

Genetic Science Learning Center. (2013, February 14) Gel Electrophoresis. Retrieved September 16, 2016, from http://learn.genetics.utah.edu/content/labs/gel/

CSE format:

Gel Electrophoresis [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2013 [cited 2016 Sep 16] Available from http://learn.genetics.utah.edu/content/labs/gel/

Chicago format:

Genetic Science Learning Center. "Gel Electrophoresis." Learn.Genetics.February 14, 2013. Accessed September 16, 2016. http://learn.genetics.utah.edu/content/labs/gel/.

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Gel Electrophoresis - Learn Genetics

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