Genetics of Prostate Cancer (PDQ®) 2/3 –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

Clinical Application of Genetic Testing for Inherited Prostate Cancer

In This Section

• Criteria for Genetic Testing in Prostate Cancer
• Multigene (Panel) Testing in Prostate Cancer
• Genetic Testing for Prostate Cancer Risk Assessment
  • BRCA1 and BRCA2
  • Mismatch repair (MMR) genes
  • HOXB13
  • ATM
  • CHEK2
  • TP53
  • NBN/NBS1
  • EPCAM
• Germline Pathogenic Variants in Men With Metastatic Prostate Cancer
• Genetic Testing for Prostate Cancer Precision Oncology

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 2.[1-5] Identification of men for inherited prostate cancer genetic testing is based upon family history criteria, personal/disease characteristics, and tumor sequencing results. 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, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2 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. Somatic findings for which germline testing is considered include:

• Somatic mutations 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 2.

Table 2. Indications for Genetic Testing for Prostate Cancer Risk

ENLARGE

	Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2018)a [1]	NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian (Version 3.2019)b [3]	NCCN Prostate Cancer (Version 4.2019)c [4]	NCCN Prostate Cancer Early Detection (Version 2.2019)d [5]	European Advanced Prostate Cancer Consensus Conference (Gillessen et al. 2017)e [2]
dMMR = mismatch repair deficient; FDR = first-degree relative; HBOC = hereditary breast and ovarian cancer; MSI = microsatellite instability; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.
aGiri et al.: Specific genes to test include BRCA1/BRCA2, DNA MMR genes, ATM, and HOXB13 depending on various testing indications.
bNCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian guideline focuses on testing for BRCA1/BRCA2 pathogenic variants.
cNCCN Prostate Cancer guideline specifies that homologous recombination gene pathogenic variants and DNA MMR gene pathogenic variants include variants in the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2. Additional genes may be appropriate depending on the clinical context.
dNCCN Prostate Cancer Early Detection guideline does not specifically state which genes to test, but describes consideration of BRCA1/BRCA2 status and the status of other cancer risk genes when discussing prostate cancer screening.
eGillessen et al. endorsed the use of large panel testing including homologous recombination and DNA MMR genes.
Family History Criteria	All men with prostate cancer from families meeting established testing or syndromic criteria for HBOC; hereditary prostate cancer; and Lynch syndrome	Personal history of Gleason score ≥7 prostate cancer with: ≥1 biologic relative with ovarian, pancreatic, or metastatic prostate cancer at any age or breast cancer <50 y; or ≥2 biologic relatives with breast or prostate cancer (any grade) at any age; or Ashkenazi Jewish ancestry	≥3 cancers on the same side of the family, especially diagnoses ≤50 y: bile duct, breast, colorectal, endometrial, gastric, kidney, melanoma, ovarian, pancreatic, prostate, small bowel, or urothelial cancer	None provided	Positive family history of prostate cancer
	Men affected with prostate cancer with >2 close biologic relatives with a cancer associated with HBOC; hereditary prostate cancer, and Lynch syndrome		Ashkenazi Jewish ancestry		Positive family history of other cancer syndromes (HBOC and/or pancreatic cancer and/or Lynch syndrome)
	Prostate cancer diagnosed <55 y in an FDR		Brother, father, or multiple family members with prostate cancer <60 y
	Death <60 y from prostate cancer in an FDR		Brother, father, or multiple family members who died of prostate cancer
Disease Characteristics	All men with metastatic prostate cancer	Personal history of metastatic prostate cancer (radiographic evidence or biopsy proven)	Men with high-/very-high-risk clinically localized, regional, or metastatic disease and any men with prostate cancer with intraductal histology	None provided	Men with newly diagnosed metastatic prostate cancer (62% of panel voted in favor of genetic counseling/testing in a minority of selected patients)
	Prostate cancer diagnosed <55 y				Prostate cancer diagnosed <60 y
Tumor Characteristics	Men with prostate cancer whose somatic testing reveals the possibility of a germline variant in a cancer risk gene	BRCA1/BRCA2 somatic mutation detected in the absence of germline testing	Consider tumor testing for homologous recombination gene pathogenic variants and for MSI or dMMR in regional and metastatic disease	None provided
Screening in BRCA1 Carriers	Follow NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian guidelines	Consider prostate cancer screening starting at age 45 y	None provided	Consider beginning shared decision making about PSA screening at age 40 y
		Interval of screening determined by baseline PSA level as specified in NCCN Prostate Cancer Early Detection Version 2.2019		Consider screening at annual intervals rather than every other year
Screening in BRCA2 Carriers	Baseline PSA >40 y or 10 years prior to the earliest age of prostate cancer in the family	Recommend prostate cancer screening starting at age 45 y	None provided	Consider beginning shared decision making about PSA screening at age 40 y
	Interval of screening determined by baseline PSA level	Interval of screening determined by baseline PSA level as specified in NCCN Prostate Cancer Early Detection Version 2.2019		Consider screening at annual intervals rather than every other year
Screening in HOXB13 Carriers	Baseline PSA >40 y or 10 years prior to the earliest age of prostate cancer in the family	None provided	None provided	None provided
	Interval of screening determined by baseline PSA level

Multigene (Panel) Testing in Prostate Cancer

Since the availability of next-generation sequencing (NGS) 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] Two studies were published using data from a clinical testing laboratory database. The first study evaluated 1,328 men with prostate cancer and reported an overall pathogenic variant rate of 15.6%, including 10.9% in DNA repair genes.[8] A second study involved a larger cohort of 3,607 men with prostate cancer, some of whom had been included in the prior publication.[9] The reported pathogenic variant rate was 17.2%. Overall, pathogenic variant rates by gene were consistently reported between the two studies and were as follows: BRCA2, 4.74%; CHEK2, 2.88%; ATM, 2.03%; and BRCA1, 1.25%.[9] The most commonly aberrant gene in this cohort was BRCA2. The first publication reported associations between family history of breast cancer and high Gleason score (≥8).[8] The second publication focused on the percentage of men with pathogenic variants who met NCCN national guidelines for genetic testing and found that 229 individuals (37%) with pathogenic variants in this cohort did not meet guidelines for genetic testing.[9]

A case-control study in a Japanese population of 7,636 men with prostate cancer and 12,366 men without prostate cancer evaluated pathogenic variants in eight genes (BRCA1, BRCA2, CHEK2, ATM, NBN, PALB2, HOXB13, and BRIP1) for an association with prostate cancer.[10] The study found strong associations for BRCA2 (odds ratio [OR], 5.65; 95% confidence interval [CI], 3.55–9.32), HOXB13 (OR, 4.73; 95% CI, 2.84–8.19), and ATM (OR, 2.86; 95% CI, 1.63–5.15). The study supports a population-specific assessment of the genetic contribution to prostate cancer risk.

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 [11] and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[12] Prostate cancer in particular has been observed at higher rates in male carriers of BRCA2 pathogenic variants than in the general population.[13]

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 3.

Table 3. Case Series of BRCA Pathogenic Variants in Prostate Cancer

Study	Population	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)
BCLC = Breast Cancer Linkage Consortium; CDC = Centers for Disease Control and Prevention; CI = confidence interval; OCCR = Ovarian Cancer Cluster Region; RR = relative risk; SIR = standardized incidence ratio.
aIncludes all cancers except breast, ovarian, and nonmelanoma skin cancers.
BCLC (1999) [14]	BCLC family set that included 173 BRCA2 linkage– or pathogenic variant–positive families, among which there were 3,728 individuals and 333 cancersa	Not assessed	Overall: RR, 4.65 (95% CI, 3.48–6.22)
			Men <65 y: RR, 7.33 (95% CI, 4.66–11.52)
Thompson et al. (2001) [15]	BCLC family set that included 164 BRCA2 pathogenic variant–positive families, among which there were 3,728 individuals and 333 cancersa	Not assessed	OCCR: RR, 0.52 (95% CI, 0.24–1.00)
Thompson et al. (2002) [11]	BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were carriers of BRCA1 pathogenic variants; 1,106 were tested noncarriers, and 8,496 were not tested	Overall: RR, 1.07 (95% CI, 0.75–1.54)	Not assessed
		Men younger than 65 y: RR, 1.82 (95% CI, 1.01–3.29)
Mersch et al. (2015) [13]	Clinical genetics population at a single institution from 1997–2013. Compared cancer incidence with U.S. Statistics Report by CDC for general population cancer incidence.	SIR, 3.809 (95% CI, 0.766–11.13) (Not significant)	SIR, 4.89 (95% CI, 1.959–10.075)

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.[16] 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 BRCA founder pathogenic variants among Ashkenazi Jewish (AJ) men with prostate cancer.[17-19] Two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic 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.[20-23] (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 BRCA Ashkenazi 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.[23] 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 4 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.

Table 4. Case-Control Studies in Ashkenazi Jewish Populations of BRCA1 and BRCA2 and Prostate Cancer Risk

ENLARGE

Study	Cases/Controls	Pathogenic Variant Frequency (BRCA1)	Pathogenic Variant Frequency (BRCA2)	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; MECC = Molecular Epidemiology of Colorectal Cancer; OR = odds ratio; WAS = Washington Ashkenazi Study.
Guisti et al. (2003) [24]	Cases: 979 consecutive AJ men from Israel diagnosed with prostate cancer between 1994 and 1995	Cases: 16 (1.7%)	Cases: 14 (1.5%)	185delAG: OR, 2.52 (95% CI, 1.05–6.04)	OR, 2.02 (95% CI, 0.16–5.72)	There was no evidence of unique or specific histopathology findings within the pathogenic variant–associated prostate cancers.
	Controls: Prevalence of founder pathogenic variants compared with age-matched controls >50 y with no history of prostate cancer from the WAS study and the MECC study from Israel	Controls: 11 (0.81%)	Controls: 10 (0.74%	5282insC: OR, 0.22 (95% CI, 0.16–5.72)
Kirchoff et al. (2004) [25]	Cases: 251 unselected AJ men treated for prostate cancer between 2000 and 2002	Cases: 5 (2.0%)	Cases: 8 (3.2%)	OR, 2.20 (95% CI, 0.72–6.70)	OR, 4.78 (95% CI, 1.87–12.25)
	Controls: 1,472 AJ men with no history of cancer	Controls: 12 (0.8%)	Controls: 16 (1.1%)
Agalliu et al. (2009) [26]	Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis: 1996)	Cases: 12 (1.2%)	Cases: 18 (1.9%)	OR, 1.39 (95% CI, 0.60–3.22)	OR, 1.92 (95% CI, 0.91–4.07)	Gleason score 7–10 prostate cancer was more common in carriers of BRCA1 pathogenic variants (OR, 2.23; 95% CI, 0.84–5.86) and carriers of BRCA2 pathogenic variants (OR, 3.18; 95% CI, 1.62–6.24) than in controls.
	Controls: 1,251 AJ men with no history of cancer	Controls: 11 (0.9%)	Controls: 12 (1.0%)
Gallagher et al. (2010) [27]	Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007	Noncarriers: 806 (96.9%)	Noncarriers: 447 (98.5%)	OR, 0.38 (95% CI, 0.05–2.75)	OR, 3.18 (95% CI, 1.52–6.66)	The BRCA1 5382insC founder pathogenic variant was not tested in this series, so it is likely that some carriers of this pathogenic variant were not identified. Consequently, BRCA1-related risk may be underestimated. Gleason score 7–10 prostate cancer was more common in carriers of BRCA2 pathogenic variants (85%) than in noncarriers (57%); P = .0002. Carriers of BRCA1/BRCA2 pathogenic variants had significantly greater risk of recurrence and prostate cancer–specific death than did noncarriers.
		Cases: 6 (0.7%)	Cases: 20 (2.4%)
	Controls: 454 AJ men with no history of cancer	Controls: 4 (0.9%)	Controls: 3 (0.7%)

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.[27]

Other populations

The association between prostate cancer and pathogenic variants in BRCA1 and BRCA2 has also been studied in other populations. Table 5 summarizes studies that used case-control methods to examine the prevalence of BRCA pathogenic variants among men with prostate cancer from other varied populations.

Table 5. Case-Control Studies in Varied Populations of BRCA1 and BRCA2 and Prostate Cancer Risk

ENLARGE

Study	Cases/Controls	Pathogenic Variant Frequency (BRCA1)	Pathogenic Variant Frequency (BRCA2)	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)	Comments
CI = confidence interval; OR = odds ratio; RR = relative risk; SIR = standardized incidence ratio.
Johannesdottir et al. (1996) [28]	Cases: 75 Icelandic men diagnosed with prostate cancer <65 y, between 1983 and 1992, with available archival tissue blocks	Not assessed	Cases: 999del5 (2.7%)	Not assessed	999del5: RR, 2.5 (95% CI, 0.49–18.4)
	Controls: 499 randomly selected DNA samples from the Icelandic National Diet Survey		Controls: (0.4%)
Eerola et al. (2001) [29]	Cases: 107 Finnish hereditary breast cancer families defined as having three first- or second-degree relatives with breast or ovarian cancer at any age	Not assessed	Not assessed	SIR, 1.0 (95% CI, 0.0–3.9)	SIR, 4.9 (95% CI, 1.8–11.0)
	Controls: Finnish population based on gender, age, and calendar period–specific incidence rates
Cybulski et al. (2013) [30]	Cases: 3,750 Polish men with prostate cancer unselected for age or family history and diagnosed between 1999 and 2012	Cases: 14 (0.4%)	Not assessed	Any BRCA1 pathogenic variant: OR, 0.9 (95% CI, 0.4–1.8)	Not assessed	Prostate cancer risk was greater in familial cases and cases diagnosed <60 y.
				4153delA: OR, 5.3 (95% CI, 0.6–45.2)
	Controls: 3,956 Polish men with no history of cancer aged 23–90 y	Controls: 17 (0.4%)		5382insC: OR, 0.5 (95% CI, 0.2–1.3)
				C61G: OR, 1.1 (95% CI, 1.6–2.2)

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).[28,29,31] 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.

Table 6. Case Series of BRCA1 and BRCA2 and Prostate Cancer Risk

ENLARGE

Study	Population	Pathogenic Variant Frequency (BRCA1)	Pathogenic Variant Frequency (BRCA2)	Prostate Cancer Risk (BRCA1)	Prostate Cancer Risk (BRCA2)	Comments
CI = confidence interval; MLPA = multiplex ligation-dependent probe amplification; RR = relative risk; UK = United Kingdom.
aEstimate calculated using RR data in UK general population.
Agalliu et al. (2007) [32]	290 men (white, n = 257; African American, n = 33) diagnosed with prostate cancer <55 y and unselected for family history	Not assessed	2 (0.69%)	Not assessed	RR, 7.8 (95% CI, 1.8–9.4)	No pathogenic variants were found in African American men.
						The two men with a pathogenic variant reported no family history of breast cancer or ovarian cancer.
Agalliu et al. (2007) [33]	266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; median age at prostate cancer diagnosis, 58 y	Not assessed	0 (0%)	Not assessed	Not assessed	31 nonsynonymous variations were identified; no truncating or pathogenic variants were detected.
Tryggvadóttir et al. (2007) [34]	527 men diagnosed with prostate cancer between 1955 and 2004	Not assessed	30/527 (5.7%) carried the Icelandic founder pathogenic variant 999del5	Not assessed	Not assessed	The BRCA2 999del5 pathogenic variant was associated with a lower mean age at prostate cancer diagnosis (69 vs. 74 y; P = .002)
Kote-Jarai et al. (2011) [35]	1,832 men diagnosed with prostate cancer between ages 36 and 88 y who participated in the UK Genetic Prostate Cancer Study	Not assessed	Overall: 19/1,832 (1.03%)	Not assessed	RR, 8.6a (95% CI, 5.1–12.6)	MLPA was not used; therefore, the pathogenic variant frequency may be an underestimate, given the inability to detect large genomic rearrangements.
			Prostate cancer diagnosed ≤55 y: 8/632 (1.27%)
Leongamornlert et al. (2012) [36]	913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; included 821 cases diagnosed between ages 36 and 65 y, regardless of family history, and 92 cases diagnosed >65 y with a family history of prostate cancer	All cases: 4/886 (0.45%)	Not assessed	RR, 3.75a (95% CI, 1.02–9.6)	Not assessed	Quality-control assessment after sequencing excluded 27 cases, resulting in 886 cases included in the final analysis.
		Cases ≤65 y: 3/802 (0.37%)

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.[32]

Prostate cancer aggressiveness in carriers of BRCA pathogenic variants

The studies summarized in Table 7 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.

Table 7. Case-Control Studies of BRCA1 and BRCA2 and Prostate Cancer Aggressiveness

ENLARGE

Study	Cases / Controls	Gleason Scorea	PSAa	Tumor Stage or Gradea	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OR = odds ratio; PSA = prostate-specific antigen; UK = United Kingdom.
aMeasures of prostate cancer aggressiveness.
Tryggvadóttir et al. (2007) [34]	Cases: 30 men diagnosed with prostate cancer who were carriers of BRCA2 999del5 founder pathogenic variants	Gleason score 7–10:	Not assessed	Stage IV at diagnosis:
		— Cases: 84%		— Cases: 55.2%
	Controls: 59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 pathogenic variant	— Controls: 52.7%		— Controls: 24.6%
Agalliu et al. (2009) [26]	Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis, 1996)	Gleason score 7–10:	Not assessed	Not assessed
		— BRCA1 185delAG pathogenic variant: OR, 3.54 (95% CI, 1.22–10.31)
	Controls: 1,251 AJ men with no history of cancer	— BRCA2 6174delT pathogenic variant: OR, 3.18 (95% CI, 1.37–7.34)
Edwards et al. (2010) [37]	Cases: 21 men diagnosed with prostate cancer who harbored a BRCA2 pathogenic variant; 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series	Not assessed	PSA ≥25 ng/mL: HR, 1.39 (95% CI, 1.04–1.86)	Stage T3: HR, 1.19 (95% CI, 0.68–2.05)
				Stage T4: HR, 1.87 (95% CI, 1.00–3.48)
				Grade 2: HR, 2.24 (95% CI, 1.03–4.88)
	Controls: 1,587 age- and stage-matched men with prostate cancer			Grade 3: HR, 3.94 (95% CI, 1.78–8.73)
Gallagher et al. (2010) [27]	Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 carriers of BRCA1 pathogenic variants and 20 carriers of BRCA2 pathogenic variants	Gleason score 7–10:	Not assessed	Not assessed	The BRCA1 5382insC founder pathogenic variant was not tested in this series.
	Controls: 454 AJ men with no history of cancer	— BRCA2 6174delT pathogenic variant: HR, 2.63 (95% CI, 1.23–5.6; P = .001)
Thorne et al. (2011) [38]	Cases: 40 men diagnosed with prostate cancer who were carriers of BRCA2 pathogenic variants from 30 familial breast cancer families from Australia and New Zealand	Gleason score ≥8:	PSA 10–100 ng/mL:	Stage ≥pT3 at presentation:	Carriers of BRCA2 pathogenic variants were more likely to have high-risk disease by D’Amico criteria than were noncarriers (77.5% vs. 58.7%, P = .05).
			— BRCA2 pathogenic variants: 35% (14/40)	— BRCA2 pathogenic variants: 44.7% (17/38)
		— BRCA2 pathogenic variants: 65.8% (25/38)	— Controls: 27.9% (27/97)
			PSA >101 ng/mL:
	Controls: 97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA pathogenic variant found in the family	— Controls: 33.0% (25/97)	— BRCA2 pathogenic variants: 10% (4/40)	— Controls: 22.6% (21/97)
			— Controls: 2.1% (2/97)
Castro et al. (2013) [39]	Cases: 2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers of BRCA1 pathogenic variants and 61 were carriers of BRCA2 pathogenic variants	Gleason score >8:	BRCA1 median PSA: 8.9 (range, 0.7–3,000)	Stage ≥pT3 at presentation:	Nodal metastasis and distant metastasis were higher in men with a BRCA pathogenic variant than in controls.
		— BRCA1 pathogenic variants: 27.8% (5/18)		— BRCA1: 38.9% (7/18)
		— BRCA2 pathogenic variants: 37.7% (23/61)	BRCA2 median PSA: 15.1 (range, 0.5–761)	— BRCA2 : 49.2% (30/61)
	Controls: 1,940 men who were BRCA1/BRCA2 noncarriers	— Controls 15.4% (299/1,940)	Controls median PSA: 11.3 (range, 0.2–7,800)	— Controls: 31.7% (616/1,940)
Akbari et al. (2014) [40]	Cases: 4,187 men who underwent prostate biopsy for elevated PSA or abnormal exam, including 26 men with at least one BRCA coding pathogenic variant (all 26 coding exons of BRCA were sequenced for polymorphisms)	Gleason score 7–10:	Cases median PSA: 56.3	Not fully assessed in cases and controls	The 12-year survival for men with a BRCA2 pathogenic variant was inferior to that of men without a BRCA2 pathogenic variant (61.8% vs. 94.3%; P < 10−4). Among the men with high-grade disease (Gleason 7–9), the presence of a BRCA2 pathogenic variant was associated with an HR of 4.38 (95% CI, 1.99–9.62; P < .0001) after adjusting for age and PSA level.
		— Cases 96%
	Controls: 1,878 men with no BRCA coding pathogenic variants (all 26 coding exons of BRCA were sequenced for polymorphisms)	— Controls 54%	Controls median PSA: 13.3

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.[41]

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 BRCA2 pathogenic 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.[42] The case-control studies summarized in Table 8 further assess this observation.

Table 8. Case-Control Studies of BRCA1 and BRCA2 and Survival Outcomes

ENLARGE

Study	Cases	Controls	Prostate Cancer–Specific Survival	Overall Survival	Comments
AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen; UK = United Kingdom.
Tryggvadóttir et al. (2007) [34]	30 men diagnosed with prostate cancer who were carriers of BRCA2 999del5 founder pathogenic variants	59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 pathogenic variant	BRCA2 999del5 pathogenic variant was associated with a higher risk of death from prostate cancer (HR, 3.42; 95% CI, 2.12–5.51), which remained after adjustment for tumor stage and grade (HR, 2.35; 95% CI, 1.08–5.11)	Not assessed
Edwards et al. (2010) [37]	21 men diagnosed with prostate cancer who harbored a BRCA2 pathogenic variant: 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series	1,587 age- and stage-matched men with prostate cancer	Not assessed	Overall survival was lower in carriers of BRCA2 pathogenic variants (4.8 y) than in noncarriers (8.5 y); in noncarriers, HR, 2.14 (95% CI, 1.28–3.56; P = .003)
Gallagher et al. (2010) [27]	832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which 6 were carriers of BRCA1 pathogenic variants and 20 carriers of BRCA2 pathogenic variants	454 AJ men with no history of cancer	After adjusting for stage, PSA, Gleason score, and therapy received:	Not assessed	The BRCA1 5382insC founder pathogenic variant was not tested in this series.
			– Carriers of BRCA1 185delAG pathogenic variants had a greater risk of death due to prostate cancer (HR, 5.16; 95% CI, 1.09–24.53; P = .001)
			— Carriers of BRCA2 6174delT pathogenic variants had a greater risk of death due to prostate cancer (HR, 5.48; 95% CI, 2.03–14.79; P = .001)
Thorne et al. (2011) [38]	40 men diagnosed with prostate cancer who were carriers of BRCA2 pathogenic variants from 30 familial breast cancer families from Australia and New Zealand	97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA pathogenic variant found in the family	BRCA2 carriers were shown to have an increased risk of prostate cancer–specific mortality (HR, 4.5; 95% CI, 2.12–9.52; P = 8.9 × 10-5), compared with noncarrier controls	BRCA2 carriers were shown to have an increased risk of death (HR, 3.12; 95% CI, 1.64–6.14; P = 3.0 × 10-4), compared with noncarrier controls	There were too few BRCA1 carriers available to include in the analysis.
Castro et al. (2013) [39]	2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers of BRCA1 pathogenic variants and 61 were carriers of BRCA2 pathogenic variants	1,940 men who were BRCA1/BRCA2 noncarriers	Prostate cancer–specific survival at 5 y:	Overall survival at 5 y:	For localized prostate cancer, metastasis-free survival was also higher in controls than in carriers of pathogenic variants (93% vs. 77%; HR, 2.7).
			— BRCA1: 80.8% (95% CI, 56.9%–100%)	— BRCA1: 82.5% (95% CI, 60.4%–100%)
			— BRCA2: 67.9% (95% CI 53.4%–82.4%)	— BRCA2: 57.9% (95% CI, 43.4%–72.4%)
			— Controls: 90.6% (95% CI 88.8%–92.4%)	— Controls: 86.4% (95% CI, 84.4%–88.4%)
Castro et al. (2015) [43]	1,302 men from the UK with local or locally advanced prostate cancer, including 67 carriers of BRCA1/BRCA2 pathogenic variants	1,235 men who were BRCA1/BRCA2 noncarriers	Prostate cancer–specific survival:	Not assessed
			— BRCA1/BRCA2: 61% at 10 y
			— Noncarriers: 85% at 10 y

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.[44] 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.[45] 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 BRCA1 variants, 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.[46] 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.[44]

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.[47,48] 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.[49] 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.[50] 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.[51] Other studies are attempting to characterize rates of prostate cancer in Lynch syndrome families and correlate molecular features with prostate cancer risk.[52]

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.[53] 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.[54] 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).[55] 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 MSH2 pathogenic variants (RR, 5.8; 95% CI, 2.6–20.9); the RRs in carriers of MLH1 and MSH6 pathogenic 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 index prostate cancer patients remain to be determined.

A study of 1,133 primary prostate adenocarcinomas and 43 neuroendocrine prostate cancers (NEPC) conducted screening by MSH2 immunohistochemistry with confirmation by NGS.[56] MSI was assessed by polymerase chain reaction and NGS. Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other Gleason scores (P < .05). Three patients had germline variants in MSH2, of whom two had a primary Gleason score of 5. Pending further confirmation, these findings may support universal MMR screening of prostate cancer with a Gleason score of 9 to 10 to identify men who may be eligible for immunotherapy and germline testing.

HOXB13

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[44] 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.[57] 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).[58] 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%.[58]

A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[59] 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.[58,60-65] This pathogenic variant appears to be restricted to white men, primarily of European descent.[58,60-62] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases.[63] 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.[64]

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.[66] 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.[64] 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).[61] 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).[67] 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.[68] 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.[69] In addition, one study identified no men of AJ ancestry who carried the G84E pathogenic variant.[70] 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).[71] 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.[72] Another study from Australia reported an age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.[73]

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.[74] In the presence of DNA damage, the ATM protein is involved in mediating cell cycle arrest, DNA repair, and apoptosis.[75] 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).[75] 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.[76] 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).[77] 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).[78]

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.[79]

Further evidence supports an association between prostate cancer and germline TP53 pathogenic variants,[80-82] although additional studies to clarify the association with this gene are warranted.

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 MSH2 promoter resulting in MSH2 protein loss.[83] (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.[55] (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.[84] 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.[85] 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 9. 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.

Table 9. Summary of Tumor Sequencing Studies With Germline Findings

Study	Cohort	Germline Results for Prostate Cancer		Comments
mCRPC = metastatic castration-resistant prostate cancer.
aPotential overlap of cohorts.
Robinson et al. (2015)a [84]	Whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 men with mCRPC	8% had germline pathogenic variants:
		— BRCA2: 9/150 (6.0%)
		— ATM: 2/150 (1.3%)
		— BRCA1: 1/150 (0.7%)
Pritchard et al. (2016)a [7]	692 men with metastatic prostate cancer, unselected for family history; analysis focused on 20 genes involved in maintaining DNA integrity and associated with autosomal dominant cancer–predisposing syndromes	82/692 (11.8%) had germline pathogenic variants:		Frequency of germline pathogenic variants in DNA repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer in the Cancer Genome Atlas (P < .001).
		— BRCA2: 37/692 (5.3%)
		— ATM: 11/692 (1.6%)
		— BRCA1: 6/692 (0.9%)
Schrader et al. (2016) [86]	1,566 patients undergoing tumor profiling (341 genes) with matched normal DNA at a single institution; 97 cases of prostate cancer included	10/97 (10.3%) had germline pathogenic variants:
		— BRCA2: 6/97 (6.2%)
		— BRCA1: 1/97 (1.0%)
		— MSH6: 1/97 (1.0%)
		— MUTYH: 1/97 (1.0%)
		— PMS2: 1/97 (1.0%)

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.[87] 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. Multiple studies have reported outcomes regarding prostate cancer treatment on the basis of germline variant status primarily among men with metastatic, castration-resistant prostate cancer, although emerging studies are focusing on the early-treatment setting. Multiple genetically informed clinical trials are under way for men with prostate cancer.[88] Table 10 summarizes some of the published precision oncology and precision management studies.

Table 10. Summary of Precision Oncology or Precision Management Studies Involving Germline Pathogenic Variant Status

Study	Cohort	Germline Results	Comments
ADT = androgen deprivation therapy; AR = androgen receptor; CSS = cause-specific survival; DDR = DNA damage repair; HR = hazard ratio; mCRPC = metastatic castration-resistant prostate cancer; mPC = metastatic prostate cancer; OS = overall survival; PFS = progression-free survival; PSA = prostate-specific antigen; RR = relative risk.
Annala et al. (2017) [89]	319 men with mCRPC; performed germline sequencing of 22 DNA repair genes	24/319 (7.5%) had DDR germline pathogenic variants:	Patients with DNA repair defects had decreased responses to ADT:
		— BRCA2: 16/319 (5.0%)	— Time from ADT initiation to mCRPC (mo): Germline positive, 11.8 (n = 22) vs. germline negative, 19.0 (n = 113) (P = .031).
		— ATM: 1/319 (0.3%)	— PFS on first-line AR-targeted therapy (mo): Germline positive, 3.3 vs. germline negative, 6.2 (P = .01).
		— BRCA1: 1/319 (0.3%)
		— PALB2: 2/319 (0.6%)
Antonarakis et al. (2018) [90]	172 men with mCRPC beginning treatment with abiraterone or enzalutamide	22/172 (12.8%) had DDR germline pathogenic variants:	In propensity score–weighted multivariable analyses, outcomes were superior in men with germline BRCA1/BRCA2/ATM variants with respect to PSA-PFS (HR, 0.48; 95% CI, 0.25–0.92; P = .027), PFS (HR, 0.52; 95% CI, 0.28–0.98; P = .044), and OS (HR, 0.34; 95% CI, 0.12–0.99; P = .048). These results were not observed for men with non-BRCA1/BRCA2/ATM germline variants (all P > .10). Study limited by the small number of patients (n = 9) with BRCA1/BRCA2/ATM variants.
		— BRCA1/BRCA2/ATM: 9/172 (5.2%)
Mateo et al. (2018) [91]	390 men with mPC; retrospective chart review	60/390 (15.4%) had germline DDR pathogenic variants:	Similar findings were observed for DDR pathogenic variant carriers and noncarriers for several outcome measures:
			— Median OS from castration resistance (3.2 y in carriers vs 3.0 y in noncarriers; P = .73).
			— Median docetaxel PFS (6.8 mo in carriers vs. 5.1 mo in noncarriers).
		— BRCA2: 37/390 (9.5%)	— RRs for prostate cancer (61% in carriers vs. 54% in noncarriers).
			— Median PFS on first-line abiraterone/enzalutamide (8.3 mo in both carriers and noncarriers).
			— RR of prostate cancer on first-line abiraterone/enzalutamide (46% in carriers vs. 56% in noncarriers).
Castro et al. (2019) [92]	419 men with mCRPC	68/419 (16.2%) had germline DDR pathogenic variants:	CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 mo vs. 33.2 mo; P = .264). CSS was halved in BRCA2 carriers (17.4 mo vs. 33.2 mo; P = .027), and BRCA2 variants were identified as an independent prognostic factor for CSS (HR, 2.11; P = .033). Significant interactions between BRCA2 status and treatment type (androgen signaling inhibitor vs. taxane therapy) were observed (CSS adjusted P = .014; PFS adjusted P = .005). CSS (24.0 mo vs. 17.0 mo) and PFS (18.9 mo vs. 8.6 mo) were greater in BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes.
		— BRCA2: 14/419 (3.3%)
		— ATM: 8/419 (1.9%)
		— BRCA1: 4/419 (1%)
		— PALB2: None

Genetic results are increasingly informing treatment and management strategies for prostate cancer. Confirmation of somatic mutations 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 2.

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