Genetics of Prostate Cancer (PDQ®) 2/5 —Health Professional Version - National Cancer Institute

Genetics of Prostate Cancer (PDQ®)—Health Professional Version - National Cancer Institute

Genetics of Prostate Cancer (PDQ®)–Health Professional Version

Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk

In This Section

• Linkage Analyses
  • Introduction to linkage analyses
  • Susceptibility loci identified in linkage analyses
• Case-Control Studies
  • Genes interrogated in case-control studies
• Admixture Mapping
• Genome-wide Association Studies (GWAS)
  • Overview
  • Introduction to GWAS
  • Susceptibility loci identified in GWAS
  • Clinical application of GWAS findings
  • Modified approaches to GWAS
  • Conclusions
• Inherited Variants Associated With Prostate Cancer Aggressiveness

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:

1. Three or more affected first-degree relatives (father, brother, son).
2. Affected relatives in three successive generations of either maternal or paternal lineages.
3. 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.

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]

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.

Table 2. Case-Control Studies in Genes With Some Association With Prostate Cancer Risk

ENLARGE

Gene	Location	Study	Cases	Controls	Prostate Cancer Associations	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OR = odds ratio; PSA = prostate-specific antigen; SNP = single nucleotide polymorphism.
AMACR	5p13.3	Zheng et al. (2002) [70]	159 U.S. men with familial prostate cancer and 245 men with sporadic prostate cancer	211 men without prostate cancer who are participants in a prostate cancer screening program	Not assessed	Genotype frequencies that compared familial prostate cancer cases to unaffected controls found four missense variants associated with familial prostate cancer (M9V, G1157D, S291L, and K277E).
		Daugherty et al. (2007) [71]	1,318 U.S. men aged <55 y with prostate cancer (1,211 non-Hispanic whites and 107 non-Hispanic blacks) unselected for family history	1,842 U.S. men without prostate cancer who participated in a prostate cancer screening program (1,433 non-Hispanic whites and 409 non-Hispanic blacks)	No association was detected between any of the SNPs (M9V, IVS+169G>T, D175G, S201L, Q239H, IVS4+3803C>G, and K277E) and prostate cancer.	Risk of prostate cancer was reduced in men who regularly used ibuprofen who also had specific alleles in four SNPs (M9V, D175G, S201L, and K77E) or a specific six-SNP haplotype (TGTGCG).
		Levin et al. (2007) [72]	449 U.S. white men with familial prostate cancer from 332 familial and early-onset prostate cancer families	394 unaffected brothers of the men with prostate cancer	SNP rs3195676 (M9V):
					OR, 0.58 (95% CI, 0.38–0.90; P= .01 for a recessive model)
CHEK2	22q12.1	Dong et al. (2003) [73]	84 prostate cancer tumors; 92 prostate cancer tumors diagnosed in men younger than 59 y; 400 U.S. men with prostate cancer and no prostate cancer family history; 298 men with prostate cancer from 149 families (two men per family)	510 U.S. men without prostate cancer with a negative prostate cancer screening exam	18 CHEK2pathogenic variants were identified in 4.8% (28 of 578) of prostate cancer patients, 0 of 423 unaffected men, and 9 of 149 prostate cancer families.	157T was detected in equal numbers of cases and controls and was therefore reported to likely represent a polymorphism.
		Cybulski et al. (2013) [74]	3,750 Polish men with prostate cancer	3,956 Polish men with no history of cancer	Any CHEK2pathogenic variant: OR, 1.9 (95% CI, 1.6–2.2; P < .0001)
					Prostate cancer diagnosed <60 y: OR, 2.3 (95% CI, 1.8–3.1; P < .0001)
					Familial prostate cancer: OR, 2.7 (95% CI, 2.0–3.7; P < .0001)
EMSY	11q13.5	Nurminen et al. (2011) [75]	Initial Screen: 184 Finnish men with familial prostate cancer	923 male blood donors from the Finnish Red Cross with no cancer history	IVS6-43A>G:	IVS6-43A>G also associated with increased risk of aggressive prostate cancer (PSA ≥20 or Gleason score ≥7) in cases unselected for family history (OR, 6.5; 95% CI, 1.5–28.4; P= .002).
			Validation: 2,113 unselected prostate cancer cases		Familial cases: OR, 7.5 (95% CI, 1.3–45.5; P= .02)
		Nurminen et al. (2013) [76]	2,716 unselected Finnish men with prostate cancer	908 male blood donors from the Finnish Red Cross with no cancer history	rs10899221: OR, 1.29 (95% CI, 1.10–1.52); P = .008
					rs72944738: OR, 1.26 (95% CI, 1.04–1.52); P = .03
			1,318 Finnish men with prostate cancer who participated in the PSA screening arm of the European Randomized Study of Screening for Prostate Cancer		rs10899221: OR, 1.40 (95% CI, 1.16–1.69); P = .002
					rs72944738: OR, 1.46 (95% CI, 1.16–1.69); P = .003
KLF6	10p15	Narla et al. (2005) [77]	1,253 U.S. men with sporadic prostate cancer and 882 men with familial prostate cancer from 294 unrelated families	1,276 men with no cancer history	IVS1-27G>A:
					Familial cases: OR, 1.61 (95% CI, 1.20–2.16; P= .01)
					Sporadic cases: OR, 1.41 (95% CI, 1.08–2.00; P = .01)
		Bar-Shira et al. (2006) [78]	402 Israeli men with prostate cancer (251 AJ, 151 non-AJ)	300 Israeli women aged 20–45 y (200 AJ, 100 non-AJ)	IVS1-27G>A:
					AJ only: OR, 0.60 (95% CI, 0.35–1.03; P = .047)
					Combined cohort: OR, 0.64 (95% CI, 0.42–0.98; P = .047)
NBN/NBS1	8q21	Hebbring et al. (2006) [79]	1,819 U.S. and European men with familial prostate cancer from 909 families and 1,218 U.S. and European men with sporadic prostate cancer	697 controls consisting of a mix of U.S. and European population-based controls and unaffected men from prostate cancer families	657del5 was not detected in the control population; therefore, testing for an association was not possible.	657del5 had a carrier frequency of 0.22% (2 of 909) for familial prostate cancer and 0.25% (3 of 1,218) for sporadic prostate cancer.
		Cybulski et al. (2013) [74]	3,750 Polish men with prostate cancer	3,956 Polish men with no history of cancer	675del5: OR, 2.5 (95% CI, 1.5–4.0; P = .0003)	NBN pathogenic variants were associated with a higher mortality (HR, 1.85) and lower 5-year survival (HR, 2.08).
					Prostate cancer diagnosed <60 y: OR, 3.1 (95% CI, 1.5–6.4; P = .003)
					Familial prostate cancer: OR, 4.3 (95% CI, 2.0–9.0; P = .0001)

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:

• 5q35 (Z-score = 3.1) [83]
• 7q31 (Z-score = 4.6) [83]
• 8q24 (LOD score = 7.1) [83,84]

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 catalogExit Disclaimer 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:

1. 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]
2. 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.
3. 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 catalogExit Disclaimer.

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 catalogExit Disclaimer.

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.

Inherited Variants Associated With Prostate Cancer Aggressiveness

Prostate cancer is biologically and clinically heterogeneous. Many tumors are indolent and are successfully managed with observation alone. Other tumors 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 because sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers because they are present, easily detectable, and static throughout life.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. As described below, germline SNPs associated with prostate cancer aggressiveness are derived primarily from three methods of analysis: 1) annotation of common variants within candidate risk genes; 2) assessment of known overall prostate cancer risk SNPs for aggressiveness; and 3) GWAS for prostate cancer aggressiveness. Further work is needed to validate findings and assess these associations prospectively.

Like studies of the genetics of overall prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes.[68,140-145] Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain overall risk SNPs were also associated with aggressiveness.[146-153]

There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer.

Associations between inherited variants and prostate cancer aggressiveness have been reported. A multistage, case-only GWAS led by the National Cancer Institute examined 12,518 prostate cancer cases and discovered an association between genotype and Gleason score at two polymorphisms: rs35148638 at 5q14.3 (RASA1, P = 6.49 × 10-9) and rs78943174 at 3q26.31 (NAALADL2, P = 4.18 × 10-8).[154] Although the associations discovered in this trial may provide valuable insight into the biology of high-grade disease, it is unclear whether they will prove clinically useful. This study raises the issue of the definition of “prostate cancer aggressiveness.” Gleason score is used as a prognostic marker but is not a perfect surrogate for prostate cancer–specific survival or overall survival.

A few GWAS designed specifically to focus on prostate cancer subjects with documented disease-related outcomes have been launched. In one study—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 significantly associated with prostate cancer–specific survival.[155] Similarly, in a smaller study assessing prostate cancer–specific mortality (196 lethal cases, 368 long-term survivors), no variants were significantly associated with outcome.[156] More recently, a GWAS was conducted across 24,023 prostate cancer patients and similarly found no significant association between genetic variants and prostate cancer survival.[154] The authors of these studies concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%).

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