Genetics of Prostate Cancer (PDQ®)–Health Professional Version
Clinical Application of Genetic Testing for Inherited Prostate Cancer
Criteria for Genetic Testing in Prostate Cancer
The criteria for consideration of genetic testing for prostate cancer susceptibility varies depending on the emerging guidelines and expert opinion consensus as summarized in Table 3.[1-5] Identification of men for inherited prostate cancer genetic testing is based upon family history criteria, personal/disease characteristics, and tumor sequencingresults. Actual genes to test vary on the basis of specific guidelines or consensus conference recommendations. The National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer guideline is focused on BRCA1/BRCA2 testing on the basis of various testing criteria.[3] The NCCN Prostate Cancer treatment guideline states to test BRCA1/BRCA2, ATM, PALB2, and FANCA for men meeting specific testing indications.[4] A 2017 consensus conference addressed the role of genetic testing for inherited prostate cancer.[1] Family history–based indications for testing included testing for BRCA1/BRCA2, HOXB13, or DNA mismatch repair (MMR) genes. Tumor sequencing with potential findings of germline variants in BRCA1/BRCA2 or DNA MMR genes, as well as other genes, is recommended for confirmatory germline testing. Somaticfindings for which germline testing is considered include:
- Somatic variants that are associated with germline susceptibility.
- Hypermutated tumors, which are indicative of DNA MMR.
- Chromosome rearrangements in specific tumors.
- High-variant allele frequency (percent of sequence reads that have the identified variant). Variant allele frequency can be altered for reasons not associated with germline variants such as loss of heterozygosity, ploidy (copy number variants), tumor heterogeneity, and tumor sample purity.[6]
HOXB13 and ATM had lower level of consensus for testing on the basis of tumor sequencing. Men with metastatic castration-resistant prostate cancer were recommended to undergo genetic testing for BRCA1/BRCA2 (higher level of consensus) and ATM (moderate level of consensus). A second consensus conference focused on advanced prostate cancer stated that among panelists that recommended genetic testing on the basis of various criteria, there was agreement to use large panel testing including homologous recombination and DNA MMR genes.[2] Available genetic testing indications from guidelines and consensus conferences are shown in Table 3.
Multigene (Panel) Testing in Prostate Cancer
Since the availability of next-generation sequencing and the elimination of patent restrictions, several clinical laboratories now offer genetic testing through multigene panels at a cost comparable to single-gene testing. A caveat is the possible finding of a variant of uncertain significance, where the clinical significance remains unknown. (Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations, and research examining the use of multigene testing.) This section summarizes the evidence for additional genes that may be on prostate cancer susceptibility panel tests.
One retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis assessed the incidence of germline pathogenic variants in 16 DNA repair genes. Pathogenic variants were identified in 11.8% (82 of 692), a rate higher than in men with localized prostate cancer (4.6%, P < .001), suggesting that genetic aberrations are more commonly observed in men with aggressive forms of disease.[7]
Genetic Testing for Prostate Cancer Risk Assessment
Genetic testing for pathogenic variants in genes with some association with prostate cancer risk is now available and has the potential to identify men at increased risk of prostate cancer. Research from selected cohorts has reported that prostate cancer risk is elevated in men with pathogenic variants in BRCA1, BRCA2, and on a smaller scale, in MMR genes. Because clinical genetic testing is available for these genes, information about risk of prostate cancer on the basis of alterations in these genes is included in this section. In addition, pathogenic variants in HOXB13 are reported to account for a small proportion of hereditary prostate cancer. This section summarizes the evidence for these genes and additional genes that may be on prostate cancer susceptibility panel tests.
BRCA1 and BRCA2
Studies of male carriers of BRCA1 [8] and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[9] Prostate cancer in particular has been observed at higher rates in male carriers of BRCA2 pathogenic variants than in the general population.[10]
BRCA–associated prostate cancer risk
The risk of prostate cancer in carriers of BRCA pathogenic variants has been studied in various settings.
In an effort to clarify the relationship between BRCA pathogenic variants and prostate cancer risk, findings from several case series are summarized in Table 4.
Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline pathogenic variants in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[13] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.
One study has assessed the relationship between germline DNA repair gene pathogenic variants and metastatic prostate cancer. Of 692 men unselected for cancer family history or age at diagnosis, 5.3% (37 of 692) were found to have a BRCA2 pathogenic variant, and 0.9% (6 of 692) had a BRCA1 pathogenic variant.[7]
Prevalence of BRCA founder pathogenic variants in men with prostate cancer
Ashkenazi Jewish population
Several studies in Israel and in North America have analyzed the frequency of BRCAfounder pathogenic variants among Ashkenazi Jewish (AJ) men with prostate cancer.[14-16] Two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2pathogenic variant (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these pathogenic variants in the general Jewish population are 0.9% (95% confidence interval [CI], 0.7%–1.1%) for the 185delAG pathogenic variant, 0.3% (95% CI, 0.2%–0.4%) for the 5382insC pathogenic variant, and 1.3% (95% CI, 1.0%–1.5%) for the BRCA2 6174delT pathogenic variant.[17-20] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks (RRs) were commonly greater than 1, but only a few were statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder pathogenic variants.
In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia area who carried one of the BRCAAshkenazi founder pathogenic variants. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4%–30%) among carriers of the founder pathogenic variants and 3.8% (95% CI, 3.3%–4.4%) among noncarriers.[20] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female carriers at the same age (16% by age 70 y; 95% CI, 6%–28%). The risk of prostate cancer in male carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder pathogenic variants. Prostate cancer risk differed depending on the gene, with BRCA1 pathogenic variants associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 pathogenic variant began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).
The studies summarized in Table 5 used similar case-control methods to examine the prevalence of Ashkenazi founder pathogenic variants among Jewish men with prostate cancer and found an overall positive association between carrier status of founder pathogenic variants and prostate cancer risk.
These studies support the hypothesis that prostate cancer occurs excessively among carriers of AJ founder pathogenic variants and suggest that the risk may be greater among men with the BRCA2 founder pathogenic variant (6174delT) than among those with one of the BRCA1 founder pathogenic variants (185delAG; 5382insC). The magnitude of the BRCA2-associated risks differs somewhat, undoubtedly because of interstudy differences related to participant ascertainment, calendar time differences in diagnosis, and analytic methods. Some data suggest that BRCA-related prostate cancer has a significantly worse prognosis than prostate cancer that occurs among noncarriers.[24]
Other populations
The association between prostate cancer and pathogenic variants in BRCA1 and BRCA2 has also been studied in other populations. Table 6 summarizes studies that used case-control methods to examine the prevalence of BRCA pathogenic variants among men with prostate cancer from other varied populations.
These data suggest that prostate cancer risk in carriers of BRCA1/BRCA2 pathogenic variants varies with the location of the pathogenic variant (i.e., there is a correlation between genotype and phenotype).[25,26,28] These observations might explain some of the inconsistencies encountered in prior studies of these associations, because varied populations may have differences in the proportion of individuals with specific BRCA1/BRCA2 pathogenic variants.
Several case series have also explored the role of BRCA1 and BRCA2 pathogenic variants and prostate cancer risk.
These case series confirm that pathogenic variants in BRCA1 and BRCA2 do not play a significant role in hereditary prostate cancer. However, germline pathogenic variants in BRCA2 account for some cases of early-onset prostate cancer, although this is estimated to be less than 1% of early-onset prostate cancers in the United States.[29]
Prostate cancer aggressiveness in carriers of BRCA pathogenic variants
The studies summarized in Table 8 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 pathogenic variant.
These studies suggest that prostate cancer in carriers of BRCA pathogenic variants may be associated with features of aggressive disease, including higher Gleason score, higher prostate-specific antigen (PSA) level at diagnosis, and higher tumor stage and/or grade at diagnosis , a finding that warrants consideration as patients undergo cancer risk assessment and genetic counseling.[3] Research is under way to gain insight into the biologic basis of aggressive prostate cancer in carriers of BRCA pathogenic variants. One study of 14 BRCA2 germline pathogenic variant carriers reported that BRCA2-associated prostate cancers harbor increased genomic instability and a mutational profile that more closely resembles metastatic prostate cancer than localized disease, with genomic and epigenomic dysregulation of the MED12L/MED12 axis similar to metastatic castration-resistant prostate cancer.[38]
BRCA1/BRCA2 and survival outcomes
Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 pathogenic variants have been examined for survival. In an unadjusted analysis performed on a case series, median survival was 4 years in 183 men with prostate cancer with a BRCA2pathogenic variant and 8 years in 119 men with a BRCA1 pathogenic variant. The study suggests that carriers of BRCA2 pathogenic variants have a poorer survival than carriers of BRCA1 pathogenic variants.[39] The case-control studies summarized in Table 9 further assess this observation.
These findings suggest overall survival (OS) and prostate cancer–specific survival may be lower in carriers of pathogenic variants than in controls.
Additional studies involving the BRCA region
A genome-wide scan for hereditary prostate cancer in 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence of linkage to chromosome 17q markers.[41] The maximum logarithm of the odds (LOD) score in all families was 2.36, and the LOD score increased to 3.27 when only families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for pathogenic variants using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[42] Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancers was found to have a truncating pathogenic variant (3829delT). The remainder of the individuals harbored one or more germline BRCA1variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence of a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating variants in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.
Another study from the UM-PCGP examined common genetic variation in BRCA1.[43] Conditional logistic regression analysis and family-based association tests were performed in 323 familial prostate cancer families and early-onset prostate cancer families, which included 817 men with and without the disease, to investigate the association of single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kb region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (odds ratio [OR], 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[41]
Mismatch repair (MMR) genes
Five genes are implicated in MMR, namely MLH1, MSH2, MSH6, PMS2, and EPCAM. Germline pathogenic variants in these five genes have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in families, including endometrial, ovarian, and duodenal cancers; and transitional cell cancers of the ureter and renal pelvis. Reports have suggested that prostate cancer may be observed in men harboring an MMR gene pathogenic variant.[44,45] The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male carriers of MMR gene pathogenic variants or obligate carriers.[46] The expected number of cases among these 106 men was 1.52 (P < .01); the men were younger at the time of diagnosis (60.4 y vs. 66.6 y; P = .006) and had more evidence of Gleason score of 8 to 10 (P < .00001) than the cases from the Norwegian Cancer Registry. Kaplan-Meier analysis revealed that the cumulative risk of prostate cancer diagnosis by age 70 years was 30% in carriers of MMR gene pathogenic variants and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNPs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer.[47] To assess the contribution of prostate cancer as a feature of Lynch syndrome, one study performed microsatellite instability (MSI) testing on prostate cancer tissue blocks from families enrolled in a prostate cancer family registry who also reported a history of colon cancer. Among 35 tissue blocks from 31 distinct families, two tumors from families with MMR gene pathogenic variants were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer.[48] Other studies are attempting to characterize rates of prostate cancer in Lynch syndrome families and correlate molecular features with prostate cancer risk.[49]
One study that included two familial cancer registries found an increased cumulative incidence and risk of prostate cancer among 198 independent families with MMR gene pathogenic variants and Lynch syndrome.[50] The cumulative lifetime risk of prostate cancer (to age 80 y) was 30.0% (95% CI, 16.54%–41.30%; P = .07) in carriers of MMR gene pathogenic variants, whereas it was 17.84% in the general population, according to the Surveillance, Epidemiology, and End Results (SEER) Program estimates. There was a trend of increased prostate cancer risk in carriers of pathogenic variants by age 50 years, where the risk was 0.64% (95% CI, 0.24%–1.01%; P = .06), compared with a risk of 0.26% in the general population. Overall, the hazard ratio (HR) (to age 80 y) for prostate cancer in carriers of MMR gene pathogenic variants in the combined data set was 1.99 (95% CI, 1.31–3.03; P = .0013). Among men aged 20 to 59 years, the HR was 2.48 (95% CI, 1.34–4.59; P = .0038).
A systematic review and meta-analysis that included 23 studies (6 studies with molecular characterization and 18 risk studies, of which 12 studies quantified risk for prostate cancer) reported an association of prostate cancer with Lynch syndrome.[51] In the six molecular studies included in the analysis, 73% (95% CI, 57%–85%) of prostate cancers in carriers of MMR gene pathogenic variants were MMR deficient. The RR of prostate cancer in carriers of MMR gene pathogenic variants was estimated to be 3.67 (95% CI, 2.32–6.67). Of the twelve risk studies, the RR of prostate cancer ranged from 2.11 to 2.28, compared with that seen in the general population depending on carrier status, prior diagnosis of colorectal cancer, or unknown male carrier status from families with a known pathogenic variant.
A study from three sites participating in the Colon Cancer Family Registry examined 32 cases of prostate cancer (mean age at diagnosis, 62 y; standard deviation, 8 y) in men with a documented MMR gene pathogenic variant (23 MSH2 carriers, 5 MLH1 carriers, and 4 MSH6 carriers).[52] Seventy-two percent (n = 23) had a previous diagnosis of colorectal cancer. Immunohistochemistry was used to assess MMR protein loss, which was observed in 22 tumors (69%); the pattern of loss of protein expression was 100% concordant with the germline pathogenic variant. The RR of prostate cancer was highest in carriers of MSH2pathogenic variants (RR, 5.8; 95% CI, 2.6–20.9); the RRs in carriers of MLH1 and MSH6pathogenic variants were 1.7 (95% CI, 1.1–6.7) and 1.3 (95% CI, 1.1–5.3), respectively. Gleason scores ranged from 5 to 10; two tumors had a Gleason score of 5; 22 tumors had a Gleason score of 6 or 7; and eight tumors had a Gleason score higher than 8. Sixty-seven percent (12 of 18) of the tumors were found to have perineural invasion, and 47% (9 of 19) had extracapsular invasion.
Although the risk of prostate cancer appears to be elevated in families with Lynch syndrome, strategies for germline testing for MMR gene pathogenic variants in indexprostate cancer patients remain to be determined.
HOXB13
Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[41] Fine-mapping of this region provided strong evidence of linkage (LOD score, 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger.[53] The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins).[54] Probands from four families were discovered to have a recurrent pathogenic variant (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the pathogenic variant. The pathogenic variant status was determined in 5,083 additional cases and 2,662 controls. Carrier frequencies and ORs for prostate cancer risk were as follows:
- Men with a positive family history of prostate cancer: 2.2% versus negative: 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10-4).
- Men younger than 55 years at diagnosis: 2.2% versus older than 55 years: 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10-4).
- Men with a positive family history of prostate cancer and younger than 55 years at diagnosis: 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years: 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10-6).
- Men with a positive family history of prostate cancer and older than 55 years at diagnosis: 1.2%.
- Controls: 0.1% to 0.2%.[54]
A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[55] Within carrier families, the G84E pathogenic variant was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E pathogenic variant was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10-6).
Additional studies have emerged that better define the carrier frequency, prostate cancer risk, and penetrance associated with the HOXB13 G84E pathogenic variant.[54,56-61] This pathogenic variant appears to be restricted to white men, primarily of European descent.[54,56-58] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases.[59] A pooled analysis that included 9,016 cases and 9,678 controls of European Americans found an overall G84E pathogenic variant frequency of 1.34% among cases and 0.28% among controls.[60]
Risk of prostate cancer by HOXB13 G84E pathogenic variant status has been reported to vary by age of onset, family history, and geographical region. A validation study in an independent cohort of 9,988 cases and 61,994 controls from six studies of men of European ancestry, including 4,537 cases and 54,444 controls from Iceland whose genotypes were largely imputed, reported an OR of 7.06 (95% CI, 4.62–10.78; P = 1.5 × 10−19) for prostate cancer risk by G84E carrier status.[62] A pooled analysis reported a prostate cancer OR of 4.86 (95% CI, 3.18–7.69; P = 3.48 × 10-17) in men with HOXB13 pathogenic variants compared with noncarriers; this increased to an OR of 8.41 (95% CI, 5.27–13.76; P = 2.72 ×10-22) among men diagnosed with prostate cancer at age 55 years or younger. The OR was 7.19 (95% CI, 4.55–11.67; P = 9.3 × 10-21) among men with a positive family history of prostate cancer and 3.09 (95% CI, 1.83–5.23; P = 6.26 × 10-6) among men with a negative family history of prostate cancer.[60] A meta-analysis that included 24,213 cases and 73,631 controls of European descent revealed an overall OR for prostate cancer by carrier status of 4.07 (95% CI, 3.05–5.45; P < .00001). Risk of prostate cancer varied by geographical region: United States (OR, 5.10; 95% CI, 3.21–8.10; P < .00001), Canada (OR, 5.80; 95% CI, 1.27–26.51; P = .02), Northern Europe (OR, 3.61; 95% CI, 2.81–4.64; P < .00001), and Western Europe (OR, 8.47; 95% CI, 3.68–19.48; P < .00001).[57] In addition, the association between the G84E pathogenic variant and prostate cancer risk was higher for early-onset cases (OR, 10.11; 95% CI, 5.97–17.12). There was no significant association with aggressive disease in the meta-analysis.
Another meta-analysis that included 11 case-control studies also reported higher risk estimates for prostate cancer in HOXB13 G84E carriers (OR, 4.51; 95% CI, 3.28–6.20; P < .00001) and found a stronger association between HOXB13 G84E and early-onset disease (OR, 9.73; 95% CI, 6.57–14.39; P < .00001).[63] An additional meta-analysis of 25 studies including 51,390 cases and 93,867 controls revealed an OR for prostate cancer of 3.248 (95% CI, 2.121–3.888). The association was most significant in whites (OR, 2.673; 95% CI, 1.920–3.720), especially those of European descent. No association was found for breast or colorectal cancer.[64] One population-based, case-control study from the United States confirmed the association of the G84E pathogenic variant with prostate cancer (OR, 3.30; 95% CI, 1.21–8.96) and reported a suggestive association with aggressive disease.[65] In addition, one study identified no men of AJ ancestry who carried the G84E pathogenic variant.[66] A case-control study from the United Kingdom that included 8,652 cases and 5,252 controls also confirmed the association of HOXB13 G84E with prostate cancer (OR, 2.93; 95% CI, 1.94–4.59; P = 6.27 × 10-8).[67] The risk was higher among men with a family history of the disease (OR, 4.53; 95% CI, 2.86–7.34; P = 3.1 × 10−8) and in early-onset prostate cancer (diagnosed at age 55 y or younger) (OR, 3.11; 95% CI, 1.98–5.00; P = 6.1 × 10−7). No association was found between carrier status and Gleason score, cancer stage, OS, or cancer-specific survival.
Penetrance estimates for prostate cancer development in carriers of the HOXB13 G84E pathogenic variant are also being reported. One study from Sweden estimated a 33% lifetime risk of prostate cancer among G84E carriers.[68] Another study from Australia reported an age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.[69]
HOXB13 plays a role in prostate cancer development and interacts with the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene identified to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility and implications for genetic counseling regarding the HOXB13 G84E pathogenic variant have yet to be defined.
ATM
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM variants.[70] In the presence of DNA damage, the ATM protein is involved in mediating cell cycle arrest, DNA repair, and apoptosis.[71] Given evidence of other cancer risks in heterozygote carriers, evidence of an association with prostate cancer susceptibility continues to emerge. (Refer to the ATM section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about ATM and breast cancer.) A prospective case series of 10,317 Danish individuals with 36 years of follow-up, during which 2,056 individuals developed cancer, found that Ser49Cys was associated with prostate cancer (HR, 2.3; 95% CI, 1.1–5.0).[71] A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found that 1.6% (11 of 692) had an ATM pathogenic variant.[7]
CHEK2
CHEK2 has also been investigated for a potential association with prostate cancer risk. A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found 1.9% (10 of 534 [men with data]) were found to have a CHEK2 pathogenic variant.[7]
TP53
TP53 has also been investigated for a potential association with prostate cancer risk. In a case series of 286 individuals from 107 families with a deleterious TP53 variant, 403 cancer diagnoses were reported, of which 211 were the first primary cancer including two prostate cancers diagnosed after age 45 years. Prostate cancer was also reported in 4 of 61 men with a second primary cancer.[72] In a Dutch case series of 180 families meeting either classic Li-Fraumeni syndrome (LFS) or Li-Fraumeni–like (LFL) family history criteria, a deleterious TP53 variant was identified in 24 families with one case of prostate cancer found in each group (LFS or LFL). Prostate cancer risks varied on the basis of the family history criteria with LFS (RR, 0.50; 95% CI, 0.01–3.00) and LFL (RR, 4.90; 95% CI, 0.10–27.00).[73] In a French case series of 415 families with a deleterious TP53 variant, four prostate cancers were reported, with a mean age at diagnosis of 63 years (range, 57–71 y).[74]
Germline TP53 pathogenic variants have also been identified in men with prostate cancer who have undergone tumor testing. A prospective case series of 42 men with either localized, biochemically recurrent, or metastatic prostate cancer unselected for cancer family history or age at diagnosis undergoing tumor-only somatic testing found that 2 of 42 men (5%) were found to have a suspected TP53 germline pathogenic variant.[75]
NBN/NBS1
NBN, which is also known as NBS1 (Nijmegan breakage syndrome 1), has been investigated for a potential association with risk of prostate cancer. A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found that 0.3% (2 of 692 men) had a NBN pathogenic variant.[7]
EPCAM
EPCAM (epithelial cellular adhesion molecule) testing has been included in some multigene panels likely due to EPCAM variants silencing MSH2. Specific large genomic rearrangement variants at the 3’ end of EPCAM, which lies near MSH2, induce methylation of the MSH2promoter resulting in MSH2 protein loss.[79] (Refer to the EPCAM section in the PDQ summary on Genetics of Colorectal Cancer for a more detailed discussion about EPCAM and Lynch syndrome.) Pathogenic variants in MSH2 that are associated with Lynch syndrome were found to be associated with increased risk of prostate cancer.[52] (Refer to the Mismatch Repair genes section of this summary for information about MSH2 and prostate cancer risk.) Thus far, studies ascertaining the spectrum of germline pathogenic variants in men with prostate cancer have not identified pathogenic variants in EPCAM.[7]
Germline Pathogenic Variants in Men With Metastatic Prostate Cancer
The metastatic prostate cancer setting is also contributing insights into the germline pathogenic variant spectrum of prostate cancer. Clinical sequencing of 150 metastatic tumors from men with castrate-resistant prostate cancer identified alterations in genes involved in DNA repair in 23% of men.[80] Interestingly, 8% of these variants were pathogenic and present in the germline. Another study focused on tumor-normal sequencing of advanced and metastatic cancers identified germline pathogenic variants in 19.6% of men (71 of 362) with prostate cancer.[81] Germline pathogenic variants were found in BRCA1, BRCA2, MSH2, MSH6, PALB2, PMS2, ATM, BRIP1, NBN, as well as other genes. These and other studies are summarized in Table 10. The contribution of germline variants identified from large sequencing efforts to inherited prostate cancer predisposition requires molecular confirmation of genes not classically linked to prostate cancer risk.
Genetic Testing for Prostate Cancer Precision Oncology
Targeted therapies on the basis of genetic results are increasingly driving options for treatment in oncology. With greater recognition of germline pathogenic variants in men with advanced or metastatic prostate cancer, treatment options have also expanded. Men with DNA repair pathogenic variants have been reported to have increased clinical activity to poly (ADP-ribose) polymerase (PARP) inhibitors.[84] On the basis of increasing data, olaparib was given Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for BRCA1/BRCA2 or ATM mutated metastatic prostate cancer. Furthermore, pembrolizumab has received FDA approval for MSI-high and MMR-deficient cancers, which may also have an impact on treatment options for men with metastatic prostate cancer. NCCN Prostate Cancer Treatment guidelines also include tumor testing and/or germline testing of men with regional or metastatic prostate cancer for MMR and homologous recombination repair deficiency to identify men who may be candidates for pembrolizumab or olaparib.[4] The guidelines also state to consider BRCA1/BRCA2 status in active surveillance discussions for men with very low risk to unfavorable intermediate risk of disease. Thus, genetic results are increasingly informing treatment and management strategies for prostate cancer. Confirmation of somatic variants through germline testing is needed so that additional recommendations can be made regarding cancer risk for patients and families.
For a summary of available clinical practice guidelines for genetic testing in prostate cancer, refer to Table 3.
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