martes, 26 de marzo de 2019

Genetics of Prostate Cancer (PDQ®) 2/3 —Health Professional Version - National Cancer Institute

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

National Cancer Institute

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

Inherited Variants Associated With Prostate Cancer Aggressiveness

Prostate cancer is biologically and clinically heterogeneous. Many tumors are indolent and are successfully managed with observation alone. Other tumors are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed because sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers because they are present, easily detectable, and static throughout life.
Findings to date regarding inherited risk of aggressive disease are considered preliminary. As described below, germline SNPs associated with prostate cancer aggressiveness are derived primarily from three methods of analysis: 1) annotation of common variants within candidate risk genes; 2) assessment of known overall prostate cancer risk SNPs for aggressiveness; and 3) GWAS for prostate cancer aggressiveness. Further work is needed to validate findings and assess these associations prospectively.
Like studies of the genetics of overall prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes.[68,140-145] Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain overall risk SNPs were also associated with aggressiveness.[146-153]
There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer.
Associations between inherited variants and prostate cancer aggressiveness have been reported. A multistage, case-only GWAS led by the National Cancer Institute examined 12,518 prostate cancer cases and discovered an association between genotype and Gleason score at two polymorphisms: rs35148638 at 5q14.3 (RASA1, P = 6.49 × 10-9) and rs78943174 at 3q26.31 (NAALADL2, P = 4.18 × 10-8).[154] Although the associations discovered in this trial may provide valuable insight into the biology of high-grade disease, it is unclear whether they will prove clinically useful. This study raises the issue of the definition of “prostate cancer aggressiveness.” Gleason score is used as a prognostic marker but is not a perfect surrogate for prostate cancer–specific survival or overall survival.
A few GWAS designed specifically to focus on prostate cancer subjects with documented disease-related outcomes have been launched. In one study—a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths)—no SNP was significantly associated with prostate cancer–specific survival.[155] Similarly, in a smaller study assessing prostate cancer–specific mortality (196 lethal cases, 368 long-term survivors), no variants were significantly associated with outcome.[156] More recently, a GWAS was conducted across 24,023 prostate cancer patients and similarly found no significant association between genetic variants and prostate cancer survival.[154] The authors of these studies concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%).
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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.
Table 3. 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 2.2019)b [3]NCCN Prostate Cancer (Version 4.2018)c [4]NCCN Prostate Cancer Early Detection (Version 2.2018)d [5]European Advanced Prostate Cancer Consensus Conference (Gillessen et al. 2017)e [2]
FDR = first-degree relative; HBOC = hereditary breast and ovarian cancer; MMR = mismatch repair; 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/BRCA2pathogenic 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, FANCA, MLH1, MSH2, MSH6, or PMS2.
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 CriteriaAll men with prostate cancer from families meeting established testing or syndromic criteria for HBOC; hereditary prostate cancer; and Lynch syndromePersonal 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 Jewishancestry>1 relative with breast, ovarian, or pancreatic cancer; >1 relative with a family history suggestive of Lynch syndrome (colorectal, endometrial, gastric, ovarian, pancreatic, small bowel, urothelial, kidney, or bile duct cancer)None providedPositive 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   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    
Disease CharacteristicsAll men with metastatic prostate cancerPersonal history of metastatic prostate cancer (radiographic evidence or biopsy proven)Men with high-/very-high-risk clinically localized, regional, or metastatic diseaseNone providedMen 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 CharacteristicsMen with prostate cancer whose somatic testing reveals the possibility of a germline variant in a cancer risk geneBRCA1/BRCA2somatic variant detected in the absence of germline testingConsider tumor testing for homologous recombination gene pathogenic variants and DNA MMR gene pathogenic variants in high-risk, very-high-risk, regional, or metastatic diseaseNone provided 
Screening in BRCA1 CarriersFollow NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian guidelinesConsider prostate cancer screening starting at age 45 yNone providedBRCA1/BRCA2status and status of other risk genes should be considered in screening discussions 
 Interval of screening determined by baseline PSA level as specified in NCCN Prostate Cancer Early Detection Version 2.2018   
Screening in BRCA2 CarriersBaseline PSA >40 y or 10 years prior to the earliest age of prostate cancer in the familyRecommend prostate cancer screening starting at age 45 yNone providedBRCA1/BRCA2status and status of other risk genes should be considered in screening discussions 
Interval of screening determined by baseline PSA levelInterval of screening determined by baseline PSA level as specified in NCCN Prostate Cancer Early Detection Version 2.2018   
Screening in HOXB13CarriersBaseline PSA >40 y or 10 years prior to the earliest age of prostate cancer in the familyNone providedNone providedNone provided 
Interval of screening determined by baseline PSA level    

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.
Table 4. Case Series of BRCA Pathogenic Variants in Prostate Cancer
StudyPopulationProstate 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) [11]BCLC family set that included 173 BRCA2 linkage – or pathogenic variant–positive families, among which there were 3,728 individuals and 333 cancersaNot assessedOverall: 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) [12]BCLC family set that included 164 BRCA2 pathogenic variant–positive families, among which there were 3,728 individuals and 333 cancersaNot assessedOCCR: RR, 0.52 (95% CI, 0.24–1.00)
Thompson et al. (2002) [8]BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were carriers of BRCA1pathogenic variants; 1,106 were tested noncarriers, and 8,496 were not testedOverall: 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) [10]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.[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.
Table 5. Case-Control Studies in Ashkenazi Jewish Populations of BRCA1 and BRCA2 and Prostate Cancer Risk
ENLARGE
StudyCases/ControlsPathogenic 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) [21]Cases: 979 consecutive AJ men from Israel diagnosed with prostate cancer between 1994 and 1995Cases: 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 IsraelControls: 11 (0.81%)Controls: 10 (0.74%5282insC: OR, 0.22 (95% CI, 0.16–5.72)
Kirchoff et al. (2004) [22]Cases: 251 unselected AJ men treated for prostate cancer between 2000 and 2002Cases: 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 cancerControls: 12 (0.8%)Controls: 16 (1.1%)
Agalliu et al. (2009) [23]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 BRCA1pathogenic variants (OR, 2.23; 95% CI, 0.84–5.86) and carriers of BRCA2pathogenic variants (OR, 3.18; 95% CI, 1.62–6.24) than in controls.
Controls: 1,251 AJ men with no history of cancerControls: 11 (0.9%)Controls: 12 (1.0%)
Gallagher et al. (2010) [24]Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007Noncarriers: 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 BRCA15382insC 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 BRCA2pathogenic variants (85%) than in noncarriers (57%); P = .0002. Carriers of BRCA1/BRCA2pathogenic 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 cancerControls: 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.[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.
Table 6. Case-Control Studies in Varied Populations of BRCA1 and BRCA2 and Prostate Cancer Risk
ENLARGE
StudyCases/ControlsPathogenic 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) [25]Cases: 75 Icelandic men diagnosed with prostate cancer <65 y, between 1983 and 1992, with available archival tissue blocksNot assessedCases: 999del5 (2.7%)Not assessed999del5: RR, 2.5 (95% CI, 0.49–18.4) 
Controls: 499 randomly selected DNA samples from the Icelandic National Diet SurveyControls: (0.4%)
Eerola et al. (2001) [26]Cases: 107 Finnish hereditary breast cancer families defined as having three first- or second-degree relatives with breast or ovarian cancer at any ageNot assessedNot assessedSIR, 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) [27]Cases: 3,750 Polish men with prostate cancer unselected for age or family history and diagnosed between 1999 and 2012Cases: 14 (0.4%)Not assessedAny BRCA1pathogenic variant: OR, 0.9 (95% CI, 0.4–1.8)Not assessedProstate 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 yControls: 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).[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.
Table 7. Case Series of BRCA1 and BRCA2 and Prostate Cancer Risk
ENLARGE
StudyPopulationPathogenic 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) [29]290 men (white, n = 257; African American, n = 33) diagnosed with prostate cancer <55 y and unselected for family historyNot assessed2 (0.69%)Not assessedRR, 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) [30]266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; median age at prostate cancer diagnosis, 58 yNot assessed0 (0%)Not assessedNot assessed31 nonsynonymous variations were identified; no truncating or pathogenic variants were detected.
Tryggvadóttir et al. (2007) [31]527 men diagnosed with prostate cancer between 1955 and 2004Not assessed30/527 (5.7%) carried the Icelandic founder pathogenic variant 999del5Not assessedNot assessedThe BRCA2999del5 pathogenic variant was associated with a lower mean age at prostate cancer diagnosis (69 vs. 74 y; P = .002)
Kote-Jarai et al. (2011) [32]1,832 men diagnosed with prostate cancer between ages 36 and 88 y who participated in the UK Genetic Prostate Cancer StudyNot assessedOverall: 19/1,832 (1.03%)Not assessedRR, 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) [33]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 cancerAll cases: 4/886 (0.45%)Not assessedRR, 3.75a(95% CI, 1.02–9.6)Not assessedQuality-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.[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.
Table 8. Case-Control Studies of BRCA1 and BRCA2 and Prostate Cancer Aggressiveness
ENLARGE
StudyCases / ControlsGleason ScoreaPSAaTumor Stage or GradeaComments
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) [31]Cases: 30 men diagnosed with prostate cancer who were carriers of BRCA2 999del5 founder pathogenic variantsGleason score 7–10:Not assessedStage 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) [23]Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis, 1996)Gleason score 7–10:Not assessedNot assessed 
– BRCA1185delAG pathogenic variant: OR, 3.54 (95% CI, 1.22–10.31)
Controls: 1,251 AJ men with no history of cancer– BRCA26174delT pathogenic variant: OR, 3.18 (95% CI, 1.37–7.34)
Edwards et al. (2010) [34]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 seriesNot assessedPSA ≥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 cancerGrade 3: HR, 3.94 (95% CI, 1.78–8.73)
Gallagher et al. (2010) [24]Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 carriers of BRCA1pathogenic variants and 20 carriers of BRCA2pathogenic variantsGleason score 7–10:Not assessedNot assessedThe BRCA15382insC founder pathogenic variant was not tested in this series.
Controls: 454 AJ men with no history of cancerBRCA26174delT pathogenic variant: HR, 2.63 (95% CI, 1.23–5.6; P= .001)
Thorne et al. (2011) [35]Cases: 40 men diagnosed with prostate cancer who were carriers ofBRCA2 pathogenic variants from 30 familial breast cancer families from Australia and New ZealandGleason score ≥8:PSA 10–100 ng/mL:Stage ≥pT3 at presentation:Carriers of BRCA2pathogenic variants were more likely to have high-risk disease by D’Amico criteriathan were noncarriers (77.5% vs. 58.7%, P = .05).
– BRCA2pathogenic variants: 35% (14/40)– BRCA2pathogenic variants: 44.7% (17/38)
– BRCA2pathogenic 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 BRCApathogenic variant found in the family– Controls: 33.0% (25/97)– BRCA2pathogenic variants: 10% (4/40)– Controls: 22.6% (21/97)
–Controls: 2.1% (2/97)
Castro et al. (2013) [36]Cases: 2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers of BRCA1pathogenic variants and 61 were carriers of BRCA2pathogenic variantsGleason score >8:BRCA1median PSA: 8.9 (range, 0.7–3,000)Stage ≥pT3 at presentation:Nodal metastasis and distant metastasis were higher in men with a BRCApathogenic variant than in controls.
– BRCA1pathogenic variants: 27.8% (5/18)– BRCA1: 38.9% (7/18)
– BRCA2pathogenic 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/BRCA2noncarriers– 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) [37]Cases: 4,187 men who underwent prostate biopsy for elevated PSA or abnormal exam, including 26 men with at least one BRCAcoding pathogenic variant (all 26 coding exons of BRCA were sequenced for polymorphisms)Gleason score 7–10:Cases median PSA: 56.3Not fully assessed in cases and controlsThe 12-year survival for men with a BRCA2pathogenic variant was inferior to that of men without a BRCA2pathogenic variant (61.8% vs. 94.3%; P < 10−4). Among the men with high-grade disease (Gleason 7–9), the presence of a BRCA2pathogenic 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.[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.
Table 9. Case-Control Studies of BRCA1 and BRCA2 and Survival Outcomes
ENLARGE
StudyCasesControlsProstate Cancer–Specific SurvivalOverall SurvivalComments
AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen; UK = United Kingdom.
Tryggvadóttir et al. (2007) [31]30 men diagnosed with prostate cancer who were carriers of BRCA2999del5 founder pathogenic variants59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2999del5 pathogenic variantBRCA2999del5 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) [34]21 men diagnosed with prostate cancer who harbored a BRCA2pathogenic 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 series1,587 age- and stage-matched men with prostate cancerNot assessedOverall survival was lower in carriers of BRCA2pathogenic 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) [24]832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which 6 were carriers of BRCA1pathogenic variants and 20 carriers of BRCA2pathogenic variants454 AJ men with no history of cancerAfter adjusting for stage, PSA, Gleason score, and therapy received:Not assessedThe BRCA15382insC 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 ofBRCA26174delT 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) [35]40 men diagnosed with prostate cancer who were carriers ofBRCA2 pathogenic variants from 30 familial breast cancer families from Australia and New Zealand97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCApathogenic variant found in the familyBRCA2carriers 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 controlsBRCA2carriers 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 controlsThere were too few BRCA1carriers available to include in the analysis.
Castro et al. (2013) [36]2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers of BRCA1pathogenic variants and 61 were carriers of BRCA2pathogenic variants1,940 men who were BRCA1/BRCA2noncarriersProstate 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) [40]1,302 men from the UK with local or locally advanced prostate cancer, including 67 carriers ofBRCA1/BRCA2pathogenic variants1,235 men who were BRCA1/BRCA2noncarriersProstate 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.[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]
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