Genetics of Prostate Cancer (PDQ®)–Health Professional Version
Executive Summary
This executive summary reviews the topics covered in this PDQ summary on the genetics of prostate cancer, with hyperlinks to detailed sections below that describe the evidence on each topic.
- Inheritance and RiskA genetic contribution to prostate cancer risk has been documented, and knowledge about the molecular genetics of the disease is increasing. Clinical management based on knowledge of inherited pathogenic variants is emerging. Factors suggestive of a genetic contribution to prostate cancer include the following: 1) multiple affected first-degree relatives (FDRs) with prostate cancer, including three successive generations with prostate cancer in the maternal or paternal lineage; 2) early-onset prostate cancer (age ≤55 y); and 3) prostate cancer with a family history of other cancers (e.g., breast, ovarian, pancreatic).
- Associated Genes and Single-Nucleotide Polymorphisms (SNPs)Several genes and chromosomal regions have been found to be associated with prostate cancer in various linkage analyses, case-control studies, genome-wide association studies (GWAS), and admixture mapping studies. Pathogenic variants in genes of high and moderate penetrance, such as BRCA1, BRCA2, the mismatch repair genes, and HOXB13 confer modest to high lifetime risk of prostate cancer. Some, such as BRCA2, have emerging clinical relevance in the treatment and screening for prostate cancer. In addition, GWAS have identified more than 100 SNPs associated with the development of prostate cancer, but the clinical utility of these findings remains uncertain. Studies are ongoing to assess whether combinations of these SNPs may have clinical relevance in identifying individuals at increased risk of the disease. Studies analyzing the association between variants and aggressive disease are also ongoing.
- Clinical ManagementInformation is limited about the efficacy of commonly available screening tests such as the digital rectal exam and serum prostate-specific antigen (PSA) levels in men genetically predisposed to developing prostate cancer. Initial reports of targeted PSA screening of carriers of BRCA pathogenic variants has yielded a higher proportion of aggressive disease. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. For example, some experts suggest initiating prostate cancer screening at age 45 years in carriers of BRCA2 pathogenic variants and consideration of screening in BRCA1 carriers. Inherited variants may influence treatment decisions, particularly for males with pathogenic variants in DNA repair genes. Studies have reported improved response rates to poly (ADP-ribose) polymerase (PARP) inhibition among males with metastatic, castrate-resistant prostate cancer carrying germline pathogenic variants in BRCA2 and other DNA repair genes.
- Psychosocial and Behavioral IssuesPsychosocial research in men at increased hereditary risk of prostate cancer has focused on risk perception, interest in genetic testing, and screening behaviors. Study conclusions vary regarding whether FDRs of prostate cancer patients accurately estimate their prostate cancer risk, with some studies reporting that men with a family history of prostate cancer consider their risk to be the same as or less than that of the average man. Factors such as being married and the confusion between benign prostatic hyperplasia and prostate cancer have been found to influence perceived risk of prostate cancer. Studies conducted before the availability of genetic testing for prostate cancer susceptibility showed that factors found to positively influence men’s hypothetical interest in genetic testing included the advice of their primary care physician, a combination of the emotional distress and concern about prostate cancer treatment effects, and having children. Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk based on family history; in general, results appear contradictory regarding whether men with a family history are more likely to be screened than those not at risk and whether the screening is appropriate for their risk status. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.
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.]
[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.]
The public health burden of prostate cancer is substantial. A total of 174,650 new cases of prostate cancer and 31,620 deaths from the disease are anticipated in the United States in 2019, making it the most frequent nondermatologic cancer among U.S. males.[1] A man’s lifetime risk of prostate cancer is one in nine. 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 patient’s 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 cancer–specific 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]
Risk Factors for Prostate Cancer
The three most important recognized risk factors for prostate cancer in the United States are:
Age
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 437 for men 49 years or younger, 1 in 59 for men aged 50 through 59 years, 1 in 22 for men aged 60 through 69 years, and 1 in 13 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 9.[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 pathogenic variants, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.
Ancestry
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]
Family history of prostate cancer
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. (Refer to 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, 2.05–2.20) with an affected father only, 2.96 (95% CI, 2.80–3.13) with an affected brother only, and 8.51 (95% CI, 6.13–11.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.26–25.67), 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, 1.0–3.0; multivariate RR, 1.7; 95% CI, 0.9–3.2). 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, 2.4–14.0).[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, 1.02–1.26).[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/BRCA2pathogenic variants 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]
- Multiple affected FDRs with prostate cancer.
- Early-onset prostate cancer (age ≤55 y).
- Metastatic prostate cancer.
- Prostate cancer with a family history of other cancers (e.g., breast, ovarian, pancreatic).
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, 1.9–3.3) with adjustment for age and ethnicity.[39]
There is little evidence that family history alone is associated with inferior clinical outcomes. In a cohort of 7,690 men in Germany who were undergoing radical prostatectomy for localized prostate cancer, family history had no bearing on prostate cancer–specific survival.[40]
Other potential modifiers of prostate cancer risk
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.[41] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[42] 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.[43] 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.[44]
(Refer to the PDQ summary on Prostate Cancer Prevention for more information about nongenetic modifiers of prostate cancer risk in the general population.)
Multiple Primaries
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, 15.0%–15.4%). 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.[45]
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).[46]
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 pathogenic variants 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.[45]
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.[47]
Data are emerging that prostate cancer patients who have at least one additional primary malignancy disproportionately harbor pathogenic variants in known cancer-predisposing genes, such as BRCA2 and MLH1.[48]
Risk of Other Cancers in Multiple-Case Families
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.[49-51]
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, 1.0–3.2). 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 site–specific disorder.[52]
A study from the Swedish Family Cancer Database reported an increased risk of the following cancers in families where multiple members had a prostate cancer diagnosis: myeloma (RR, 2.44; 95% CI, 1.24–4.82), kidney cancer (RR, 2.32; 95% CI, 1.23–4.36), nonthyroid endocrine tumors (RR, 2.18; 95% CI, 1.06–4.49), melanoma (RR, 1.82; 95% CI, 1.18–2.80), nervous system tumors (RR, 1.77; 95% CI, 1.08–2.91), and female breast cancer (RR, 1.37; 95% CI, 1.02–1.86).[53] It remains to be determined whether these associations are from a common genetic basis, shared environment, or a combination of factors.
Inheritance of Prostate Cancer Risk
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, 52%–63%) 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 y in MZ twins vs. 6.5 y 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.[54] 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 y 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.[55]
Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[56-58] 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.[54] 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 [59-62] 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 y) than noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[63]
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- Page WF, Braun MM, Partin AW, et al.: Heredity and prostate cancer: a study of World War II veteran twins. Prostate 33 (4): 240-5, 1997. [PUBMED Abstract]
- Lange EM, Salinas CA, Zuhlke KA, et al.: Early onset prostate cancer has a significant genetic component. Prostate 72 (2): 147-56, 2012. [PUBMED Abstract]
- Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998. [PUBMED Abstract]
- Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997. [PUBMED Abstract]
- Verhage BA, Baffoe-Bonnie AB, Baglietto L, et al.: Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology 57 (1): 97-101, 2001. [PUBMED Abstract]
- Gong G, Oakley-Girvan I, Wu AH, et al.: Segregation analysis of prostate cancer in 1,719 white, African-American and Asian-American families in the United States and Canada. Cancer Causes Control 13 (5): 471-82, 2002. [PUBMED Abstract]
- Cui J, Staples MP, Hopper JL, et al.: Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am J Hum Genet 68 (5): 1207-18, 2001. [PUBMED Abstract]
- Conlon EM, Goode EL, Gibbs M, et al.: Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset. Int J Cancer 105 (5): 630-5, 2003. [PUBMED Abstract]
- Valeri A, Briollais L, Azzouzi R, et al.: Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother-brother dependence. Ann Hum Genet 67 (Pt 2): 125-37, 2003. [PUBMED Abstract]
- Pakkanen S, Baffoe-Bonnie AB, Matikainen MP, et al.: Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance. Hum Genet 121 (2): 257-67, 2007. [PUBMED Abstract]
Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk
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, pathogenic variants 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 pathogenic variants 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 Clinical Application of Genetic Testing for Inherited Prostate Cancer 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.
Linkage Analyses
Introduction to linkage analyses
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 unaffectedindividuals within the extended family and looks for associations between inherited genetic markers and the disease trait. If an association between a variation at a particular chromosomal region and the disease trait is found (linkage), it provides statistical evidence that the genetic locus 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 influenced by the following:
- Family size and having a sufficient number of family members who volunteer to contribute DNA.
- The number of disease cases in each family.
- Factors related to age at diagnosis (e.g., utilization of screening).
- Gender differences in disease risk (not relevant in prostate cancer but remains relevant in linkage analysis for other conditions).
- Heterogeneity of disease in cases (e.g., aggressive vs. nonaggressive phenotype).
- Genetic heterogeneity (e.g., multiple genetic variants contribute to the same condition).
- The accuracy of family history information.
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:
- Three or more affected first-degree relatives (father, brother, son).
- Affected relatives in three successive generations of either maternal or paternal lineages.
- At least two relatives affected at age 55 years or younger.
Using these criteria, surgical series have reported that approximately 3% to 5% of men with prostate cancer 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 man’s lifetime risk of prostate cancer is one in nine,[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, obscuring the genetic signal. 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.
Susceptibility loci identified in linkage analyses
Several proposed prostate cancer susceptibility loci have been identified in families with multiple prostate cancer–affected individuals. Genes residing at risk loci discovered using linkage analysis include HPC1/RNASEL (1q25), PCAP (1q42.2-43), HPCX (Xq27-28), CAPB(1p36), and HPC20 (20q13),[12] as well as intergenic regions at 8p and 8q.[13,14] In addition, 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: 3p14, 3p24-26, 5q11-12, 5q35, 6p22.3, 7q32, 8q13, 9q34, 11q22, 15q11, 16q23, 17q21-22, and 22q12.3.[1,9,12]
Conflicting evidence exists regarding the linkage to some of these loci. Data on the proposed phenotype associated with each locus are often limited, and validation studies are needed to firmly establish associations. Evidence suggests that many of the prostate cancer risk loci discovered via linkage analysis account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.
Linkage analyses in various familial phenotypes
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).[13,15] 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.[16] Additional studies that include a larger number of African American families are needed to confirm these findings.
In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analyses have been performed in families with clinically high-risk features such as: 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 study of 123 families with two or more affected family members with aggressive prostate cancer discovered linkage at chromosome 22q11 and 22q12.3-q13.1.[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[17] Another linkage analysis utilizing a higher resolution marker set in 348 families with aggressive prostate cancer found 8q24 to be a region with strong evidence of linkage.[18] Additional regions of linkage with aggressive disease with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.
Case-Control Studies
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 genetic variant, 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:[19,20]
- Stratification of the population being studied. (Unknown population based genetic differences between cases and controls that could result in false-positive associations.)[21]
- Genetic heterogeneity. (Different alleles or loci that can result in a similar phenotype.)
- Limitations of self-identified race or ethnicity and unknown confounding variables.
Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[19,20]
Genes interrogated in case-control studies
Androgen receptor gene (AR)
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.[22] 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.[23]
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 microsatelliterepeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[24,25] 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.[22,24-34] 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], 1.1–1.3) and short GGN length (OR, 1.3; 95% CI, 1.1–1.6) 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.[35] 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.[36] 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, 1.08–1.69; P = .03).[37]
An analysis of AR gene CAG and GGN repeat length polymorphisms targeted African American men from the Flint Men’s 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.[38] 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 previous smaller studies,[36,39,40] indicate that short ARrepeat variants do not contribute significantly to the risk of prostate cancer in African American men.
Germline pathogenic variants in the AR gene (located on the X chromosome) have been rarely reported. The R726L pathogenic variant has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[41] This variant, 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 pathogenic variant in one of the familial cases and no new germline variants in the AR gene.[42] These investigators concluded that germline AR pathogenic variants 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 variant, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this variant was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[43]
Steroid 5-alpha-reductase 2 gene (SRD5A2)
Molecular epidemiology studies have also examined genetic polymorphisms of the SRD5A2gene, 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.[44] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[45,46]
A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[47] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[44,48] 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.[22,44] 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.[49] 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, 1.01–2.08; OR, 1.49; 95% CI, 1.03–2.15).[37] 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, 1.09–2.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.14–2.68).[50] 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.[51]
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, 0.35–0.88; OR, 0.57; 95% CI, 0.36–0.90; OR, 0.55; 95% CI, 0.35–0.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.94–2.63).[52] Additional studies are needed to confirm these findings.
Estrogen receptor-beta gene (ER-beta)
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.[53] This study awaits replication.
E-cadherin gene (CDH1)
Germline pathogenic variants in the tumor suppressor gene E-cadherin (CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160→A, located in the promoter region of CDH1, has been found to alter the transcriptional activity of this gene.[54] Because somatic pathogenic variants in CDH1 have been implicated in the development of invasive malignancies in a number of different cancers,[55] 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, 1.11–1.60). 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.[56] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.
Toll-like receptor genes
There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[57] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[58] 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.[59-63] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.
One study was based on 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[64] 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-10SNPs 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, 0.33–0.90). 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.
Other genes and polymorphisms interrogated for risk
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.[65] 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.[66] 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, 1.44–3.38; 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, 2.11–8.72; 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.[67]
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).[68] However, a subsequent meta-analysis of case-control studies that focused onMDM2 (T309G) and prostate cancer risk revealed no association.[69] Therefore, the biologic basis of the various associations identified requires further study.
Table 2 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, NBN, CHEK2, AR, SRD5A2, ER-beta, CDH1, 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
Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[80] 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.[81,82]
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.[85] 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.[81] (Refer to the GWAS section of this summary for more information.)
Genome-wide Association Studies (GWAS)
Overview
- GWAS can identify inherited genetic variants that influence a specific phenotype, such as risk of a particular disease.
- For complex diseases, such as prostate cancer, risk of developing the disease is the product of multiple genetic and environmental factors; each individual factor contributes relatively little to overall risk.
- To date, GWAS have discovered more than 100 common genetic variants associated with prostate cancer risk.
- Individuals can be genotyped for all known prostate cancer risk markers relatively easily; but, to date, studies have not demonstrated that this information substantially refines risk estimates from commonly used variables, such as family history.
- The clinical relevance of variants identified from GWAS remains unclear.
Introduction to GWAS
Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[86] 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.[87,88] 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 signals–in which allele frequencies deviate significantly in case compared to control populations–are 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.[89-91]
To date, over 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (refer to the National Human Genome Research Institute GWAS catalog and [92]).[93] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. In addition, men with early-onset prostate cancer have a higher cumulative number of risk alleles compared with older prostate cancer cases and compared with public controls.[94] However, the findings should be qualified with a few important considerations:
- GWAS reported thus far have been designed to identify genetic polymorphisms that are relatively common in the population. It is very unlikely that an allele with high frequency in the population by itself contributes substantially to cancer risk. This, coupled with the polygenic nature of prostate tumorigenesis, means that the contribution by any single variant identified by GWAS to date is quite small, generally with an OR for disease risk of less than 1.3. In addition, despite extensive genome-wide interrogation of common polymorphisms in tens of thousands of cases and controls, GWAS findings to date do not account for even half of the genetic component of prostate cancer risk.[92,95,96]
- Variants uncovered by GWAS are not likely to be the ones directly contributing to disease risk. As mentioned above, SNPs exist in linkage disequilibrium blocks and are merely proxies for a set of variants—both known and previously undiscovered—within a given block. The causal allele is located somewhere within that linkage disequilibrium block.
- Admixture by groups of different ancestry can confound GWAS findings (i.e., a statistically significant finding could reflect a disproportionate number of subjects in the cases versus controls, rather than a true association with disease). Therefore, GWAS subjects, by design, comprise only one ancestral group. As a result, some populations remain underrepresented in genome-wide analyses.
The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[97]
Susceptibility loci identified in GWAS
Beginning in 2006, multiple genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in European American, African American, Icelandic, and Swedish populations.[98-111] In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[110,111]
Since the discovery of prostate cancer risk loci at 8q24, more than 100 variants at 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 annotated in the National Human Genome Research Institute GWAS catalog.
GWAS in populations of non-European ancestry
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.[112] 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 annotated in the National Human Genome Research Institute GWAS catalog.
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.[84] 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.[113] Another study examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls.[114] The majority of risk alleles (approximately 83%) are shared across African American and European American populations.
Statistically well-powered GWAS have also been launched to examine inherited cancer risk in Japanese and Chinese populations. Investigators discovered that these populations share many risk regions observed in African American men in other studies.[115-117] Additionally, risk regions that are unique to these ancestral groups were identified. Ongoing work in larger cohorts will validate and expand upon these findings.
Clinical application of GWAS findings
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. As increasing numbers of risk SNPs have been discovered, they have been applied to clinical cohorts alongside traditional variables such as PSA and family history. An initial study of the first five known risk SNPs could not demonstrate that they added clinically meaningful data.[118] In later trials, larger risk-SNP panels also could not demonstrate usefulness for a large proportion of the screening population. However, the small subset of men carrying large numbers of risk alleles, especially those with positive family histories, were at appreciably high risk of developing prostate cancer.[118,119]
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.[120] 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).[121]
By 2014, approximately 100 bona fide prostate cancer risk variants had been annotated. A polygenic risk score comprising the full complement of known risk SNPs has been proposed that could account for a 2.9-fold increase in prostate cancer risk among men in the top 10% risk stratum and a 5.7-fold risk increase among men in top 1% risk stratum, compared with the population average. The authors concluded that targeted germline genetic testing, perhaps focusing on men with a family history of prostate cancer, may help improve the accuracy of PSA screening.[92] The application of a similar genetic score in the placebo arm of the Prostate Cancer Prevention Trial demonstrated that genotypes across multiple risk SNPs modestly supplement family history information when stratifying patients for prostate cancer risk.[122] Larger cohorts have validated the finding that those at the extremes of risk allele status carry appreciably greater or less prostate cancer risk, though these subsets represent a very small fraction of the overall screening population.[123,124] A 2016 analysis of a collection of risk variants suggested an association between cumulative risk allele status and early-onset prostate cancer.[125]
GWAS findings to date account for only 33% to 50% 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.[126]
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. Finally, GWAS are providing more insight into the mechanism of prostate cancer risk. Notably, almost all reported prostate cancer risk alleles reside in nonprotein-coding regions of the genome; however, the underlying biological mechanism of disease susceptibility was initially unclear. It is now apparent that a large proportion of risk variants affect the activity of regulatory elements and, in turn, distal genes.[127-130,130-135] As GWAS elucidate these networks, it is hoped that new therapies and chemopreventive strategies will follow.
Modified approaches to GWAS
A 2012 study used a novel approach to identify polymorphisms associated with risk.[136] 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 12q13.13—a locus previously implicated in cancer development—associated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.13–1.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants. Other approaches include evaluating SNPs implicated in a phenotype other than prostate cancer.[137,138]
Conclusions
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.[139] 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.
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