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Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.
Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. For more information, see OMIM.
A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term "variant" rather than the term "mutation" to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. For more information on variant classification, see Cancer Genetics Overview.
Prostate cancer is highly heritable. Up to 60% of prostate cancer risk is caused by inherited factors.[
Prostate cancer clusters with particular intensity in some families. Highly to moderately penetrant genetic variants are thought to be associated with prostate cancer risk in these families. Members of these families may benefit from genetic counseling. Additionally, polygenic risk scores derived from combinations of single nucleotide polymorphisms, in addition to other risk factors like family history, race, and age/stage of prostate cancer diagnosis, have also been developed.[
References:
Age
Prostate cancer risk correlates with age. Prostate cancer is rarely seen in men younger than 40 years. The incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 457 for men aged 49 years or younger, 1 in 55 for men aged 50 through 59 years, 1 in 19 for men aged 60 through 69 years, and 1 in 11 for men aged 70 years and older. Lifetime risk of developing prostate cancer is 1 in 8.[
Ancestry
The risk of developing prostate cancer is dramatically higher among Black individuals (176.2 cases/100,000 men) when compared with other racial and ethnic groups in the United States:
Prostate cancer mortality rates in Black individuals (37.5/100,000 men) are higher than those in other racial and ethnic groups in the United States:
Globally, prostate cancer incidence and mortality rates also vary widely from country to country.[
Family History of Prostate Cancer and Other Cancers
Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[
A meta-analysis of 33 epidemiological case-control and cohort-based studies has provided detailed information regarding risk ratios related to family history of prostate cancer (for more information, see Table 1).[
Risk Group | RR for Prostate Cancer (95% CI) |
---|---|
CI = confidence interval; FDR = first-degree relative. | |
a Adapted from Kiciński et al.[ |
|
Brother(s) with prostate cancer diagnosed at any age | 3.14 (2.37–4.15) |
Father with prostate cancer diagnosed at any age | 2.35 (2.02–2.72) |
One affected FDR diagnosed at any age | 2.48 (2.25–2.74) |
Affected FDRs diagnosed <65 y | 2.87 (2.21–3.74) |
Affected FDRs diagnosed ≥65 y | 1.92 (1.49–2.47) |
Second-degree relativesdiagnosed at any age | 2.52 (0.99–6.46) |
Two or more affected FDRs diagnosed at any age | 4.39 (2.61–7.39) |
A family history of breast cancer is also associated with increased prostate cancer risk. In the Health Professionals Follow-up Study (HPFS), comprising over 40,000 men, those with a family history of breast cancer had a 21% higher risk of developing prostate cancer overall and a 34% increased risk of developing a lethal form of prostate cancer.[
An association also exists between prostate cancer risk and colon cancer. Men with germline variants in DNA mismatch repair genes are at increased risk of developing prostate cancer.[
Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African American, White, and Asian American individuals in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[
Evidence shows that a family history of prostate cancer can be associated with inferior clinical outcomes. When patients were referred for prostate biopsy (typically due to elevated prostate-specific antigen [PSA]), men with a family history of the disease were at increased risk for high-grade prostate cancer when compared with patients without a family history.[
Genetics
There are multiple germline pathogenic variants and single nucleotide variants that are associated with prostate cancer risk. For more information about these genetic variants, see the National Human Genome Research Institute's GWAS catalog. Germline genetic testing may be indicated to assess prostate cancer risk and/or inform therapeutic decision-making in men diagnosed with prostate cancer. Prostate cancer risks vary depending on the specific gene and pathogenic variant involved.[
References:
Risk assessment for prostate cancer primarily involves the intake of a patient's family cancer history. Family history intake includes the following:
*Cancers include, but are not limited to, the following: prostate, breast, pancreas, colorectal, uterine, ovarian, upper gastrointestinal (GI), and skin cancers.
Ancestry is also an important component of the family history. Ashkenazi Jewish ancestry on either side of the family may prompt greater suspicion for founder pathogenic variants in BRCA1 and BRCA2, which could lead to increased cancer risk in a family. Men of African descent (Black men) also have a higher risk for prostate cancer. Within the United States, Black men (176.2 prostate cancer cases/100,000 men) have approximately a 70% higher incidence rate of prostate cancer than White men (103.5 prostate cancer cases/100,000 men).[
These familial risk factors are then incorporated into recommendations for prostate cancer screening. National guidelines recommend discussing prostate cancer screening with prostate-specific antigen (PSA) and digital rectal exam between the ages of 45 and 75 years for individuals at average risk for prostate cancer.
In contrast, prostate cancer screening is recommended to start at age 40 years for individuals in these high-risk groups:
Men of Black/African descent.
Men with germline pathogenic variants that increase prostate cancer risk.
Men who have family histories with features suggestive of hereditary cancer syndromes like the following:
The role of additional markers, such as polygenic risk scores, in prostate cancer risk assessment is evolving. Additional screening strategies, like multiparametric magnetic resonance imaging (mpMRI), are also being studied.
References:
The criteria for consideration of genetic testing for prostate cancer varies depending on the current guidelines and expert opinion consensus, as summarized in Table 2.[
| Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2020)a[ |
Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 2.2024)b[ |
NCCN Prostate Cancer (Version 4.2023)c[ |
European Advanced Prostate Cancer Consensus Conference (Gillessen et al. 2017[ |
---|---|---|---|---|
dMMR = mismatch repair deficient; FDR = first-degree relative; HBOC = hereditary breast and ovarian cancer; MMR = mismatch repair; MSI = microsatellite instability; NCCN = National Comprehensive Cancer Network; SDR= second-degree relative; TDR= third-degree relative. | ||||
a Giri et al.: Specific genes to test includeBRCA1/BRCA2, DNA MMR genes,ATM, andHOXB13depending on various testing indications. | ||||
b NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic guidelines state that prostate cancer risk management is indicated forBRCA1andBRCA2carriers, but evidence for risk management is insufficient for other genes. | ||||
c NCCN Prostate Cancer guidelines specify that germline multigene testing includes at least the following genes:BRCA1,BRCA2,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6, andPMS2. Including additional genes may be appropriate based on clinical context. | ||||
d Gillessen 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, or Lynch syndrome | Men affected with prostate cancer who have a family history of the following: ≥1 FDR,SDR, or TDR (on the same side of the family) with breast cancer at age ≤50 y or with any of the following: triple-negative breast cancer, ovarian cancer, pancreatic cancer, high- or very-high-risk prostate cancer, male breast cancer, or metastatic prostate cancer at any age | Men affected with prostate cancer who have the following: ≥1 FDR, SDR, or TDR (on the same side of the family) with breast cancer at age ≤50 y, colorectal or endometrial cancer at age ≤50 y, male breast cancer at any age, ovarian cancer at any age, exocrine pancreatic cancer at any age, or metastatic, regional, very-high-risk, high-risk prostate cancer at any age | Men with a positive family history of prostate cancer[ |
Men affected with prostate cancer who have >2 close biological relatives with a cancer associated with HBOC, hereditary prostate cancer, or Lynch syndrome | Men affected with prostate cancer who have ≥3 FDRs, SDRs, or TDRs (on the same side of the family) with breast cancer or prostate cancer (any grade) at any age | Men affected with prostate cancer who have ≥1 FDR with prostate cancer at age ≤60 y (exclude relatives with clinically localized Grade Group 1 disease) | Men with a positive family history of other cancer syndromes (HBOC and/or pancreatic cancer and/or Lynch syndrome)[ |
|
Men with anFDRwho was diagnosed with prostate cancer at <60 y | Men with or without prostate cancer with an FDR who meets any of the criteria listed above (except when a man without prostate cancer has relatives who meet the above criteria solely for systemic therapy decision-making; these criteria may also be extended to an affected TDR if he/she is related to the patient through two male relatives) | Men affected with prostate cancer who have ≥2 FDRs, SDRs, or TDRs (on the same side of the family) with breast cancer or prostate cancer at any age (exclude relatives with clinically localized Grade Group 1 disease) | ||
Men with relatives who died of prostate cancer | Men affected with prostate cancer who have ≥3 FDRs or SDRs (on the same side of the family) with the following Lynch syndrome-related cancers, especially if diagnosed at age <50 y: colorectal, endometrial, gastric, ovarian, exocrine pancreas, upper tract urothelial, glioblastoma, biliary tract, and small intestine | |||
Men with a metastatic prostate cancer in an FDR | ||||
Consider genetic testing in men with prostate cancer andAshkenazi Jewishancestry | Men with prostate cancer and Ashkenazi Jewish ancestry | Men with prostate cancer and Ashkenazi Jewish ancestry | ||
Men with prostate cancer and a known family history of a pathogenic or likely pathogenic variant in one of the following genes:BRCA1,BRCA2,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6,PMS2, orEPCAM | ||||
Clinical/Pathological Features | Men with metastatic prostate cancer | Men with metastatic prostate cancer | Men with metastatic prostate cancer | Men with newly diagnosed metastatic prostate cancer (62% of panel voted in favor ofgenetic counseling /testing in a minority of selected patients)[ |
Men with stage T3a or higher prostate cancer | Men with high- or very-high-risk prostate cancer | Men with high-risk prostate cancer, very-high-risk prostate cancer, high-risk localized prostate cancer, or regional (node-positive) prostate cancer | ||
Men with prostate cancer that has intraductal/ductal histology | Testing may be considered in men who have intermediate-risk prostate cancer with intraductal/cribriform histology at any age | Germline testing may be considered in men who have intermediate-risk prostate cancer with intraductal/cribriform histology at any age | ||
Germline testing may be considered in men with prostate cancer AND a prior personal history of any of the following cancers: exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal | Men with prostate cancer diagnosed at age <60 y[ |
|||
Tumor Sequencing Characteristics | Men with prostate cancer whose somatic testing reveals the possibility of a germline variant in a cancer risk gene, especiallyBRCA2,BRCA1,ATM, and DNA MMR genes | Men with a pathogenic variant found on tumor genomic testing that may have clinical implications if it is also identified in the germline | Recommend tumor testing forpathogenic variantsin homologous recombination genes in men with metastatic disease; consider tumor testing in men with regional prostate cancer | |
RecommendMSI -high or dMMR tumor testing in men with metastatic castration-resistant prostate cancer; consider testing in men with regional or castration-sensitive metastatic prostate cancer |
References:
Since next-generation sequencing (NGS) has become readily available and patent restrictions have been eliminated, several clinical laboratories offer multigene panel testing at a cost that is comparable to that of single-gene testing. Three types of genetic test results can be reported: 1) pathogenic/likely pathogenic variants, 2) variants of uncertain significance (VUS), or 3) negative results. Patients need pretest genetic counseling or informed consent to understand germline genetic testing results. For example, patients should understand that VUS can be reported, that VUS do not immediately impact care/inform cancer risk, and that VUS may be reclassified as either pathogenic/likely pathogenic or benign/likely benign when more data are acquired. For more information on genetic counseling considerations and research associated with multigene testing, see the Multigene (panel) testing section in Cancer Genetics Risk Assessment and Counseling.
Clinically Relevant Genes for Prostate Cancer
BRCA1andBRCA2
Studies of male carriers of BRCA1 and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[
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.
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; CIMBA = Consortium of Investigators of Modifiers ofBRCA1/2; OCCR = Ovarian Cancer Cluster Region; RR = relative risk; SIR = standardized incidence ratio. | |||
a Includes all cancers except breast, ovarian, and nonmelanoma skin cancers. | |||
BCLC (1999)[ |
BCLC family set that included 173BRCA2linkage – 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)[ |
BCLC family set that included 164BRCA2pathogenic 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)[ |
BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were carriers ofBRCA1pathogenic variants; 1,106 were testednoncarriers, 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)[ |
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) |
Silvestri et al. (2020)[ |
Cohort of 6,902 men who carried pathogenic variants inBRCA1orBRCA2in 53 cancer genetics groups across 33 countries | Occurred in 22.3% of carriers | Occurred in 25.6% of carriers |
Li et al. (2022)[ |
Cohort of 3,184BRCA1and 2,157BRCA2families from CIMBA; 34 of 1,508 men withBRCA1pathogenic variants and 71 of 1,063 men withBRCA2pathogenic variants had prostate cancer | RR, 0.82 (95% CI, 0.54–1.27) | RR, 2.22 (95% CI, 1.63–3.03) |
Estimates derived from the Breast Cancer Linkage Consortium may be overestimates because the data were generated from highly selected families that had significant risks of breast and ovarian cancers and were suitable for linkage analysis. A review of the relationship between BRCA2 germline pathogenic variants and prostate cancer risk suggests that BRCA2 confers a significant increase in risk among male members of HBOC families but likely plays only a small role in site-specific, multiple-case prostate cancer families.[
A meta-analysis assessed the relationship between BRCA1 and BRCA2 germline pathogenic variants and prostate cancer risk. The risk of prostate cancer was higher in BRCA2 carriers (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.03–3.47) than in BRCA1 carriers (OR, 1.35; 95% CI, 1.03–1.76).[
Prevalence ofBRCAfounder 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.[
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.[
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.
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. | ||||||
Giusti et al. (2003)[ |
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)[ |
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)[ |
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 ofBRCA1pathogenic variants (OR, 2.23; 95% CI, 0.84–5.86) and carriers ofBRCA2pathogenic 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)[ |
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) | TheBRCA15382insC 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 ofBRCA2pathogenic variants (85%) than in noncarriers (57%);P = .0002. Carriers ofBRCA1/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 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.[
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.
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)[ |
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)[ |
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)[ |
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 | AnyBRCA1pathogenic 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).[
Several case series have also explored the role of BRCA1 and BRCA2 pathogenic variants and prostate cancer risk.
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; SIR = standardized incidence ratio; UK = United Kingdom. | ||||||
a Estimate calculated using RR data in UK general population. | ||||||
b Risks calculated on men with pathogenic variants diagnosed with prostate cancer. | ||||||
Agalliu et al. (2007)[ |
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)[ |
266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; the median age at prostate cancer diagnosis was 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)[ |
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 | TheBRCA2999del5 pathogenic variant was associated with a lower mean age at prostate cancer diagnosis (69 vs. 74 y;P = .002) |
Kote-Jarai et al. (2011)[ |
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)[ |
913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; this 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%) | ||||||
Nyberg et al. (2019)[ |
Prospective cohort of men withBRCA1(n = 376) orBRCA2(n = 447) pathogenic variants from the UK and Ireland; the median follow-up was 5.9 y and 5.3 y, respectively, for prostate cancer diagnoses | Confirmed pathogenic variant: 16/376 | Confirmed pathogenic variant: 26/447 | SIR, 2.35 (95% CI, 1.43–3.88) | SIR, 4.45 (95% CI, 2.99–6.61) | Absolute prostate cancer risksb: 21% (95% CI, 13%–34%) by age 75 y and 29% (95% CI, 17%–45%) by age 85 y forBRCA1; 27% (95% CI, 17%–41%) by age 75 y and 60% (95% CI, 43%–78%) by age 85 y forBRCA2 |
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.[
Prostate cancer aggressiveness in carriers ofBRCApathogenic 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.
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. | |||||
a Measures of prostate cancer aggressiveness. | |||||
Tryggvadóttir et al. (2007)[ |
Cases: 30 men diagnosed with prostate cancer who were carriers ofBRCA2999del5 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 theBRCA2999del5 pathogenic variant | — Controls: 52.7% | — Controls: 24.6% | |||
Agalliu et al. (2009)[ |
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 | |
—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)[ |
Cases: 21 men diagnosed with prostate cancer who harbored aBRCA2 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)[ |
Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 carriers ofBRCA1pathogenic variants and 20 carriers ofBRCA2pathogenic variants | Gleason score 7–10: | Not assessed | Not assessed | TheBRCA15382insC founder pathogenic variant was not tested in this series |
Controls: 454 AJ men with no history of cancer | —BRCA26174delT pathogenic variant: HR, 2.63 (95% CI, 1.23–5.6;P = .001) | ||||
Thorne et al. (2011)[ |
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 ofBRCA2pathogenic variants were more likely to have high-risk disease byD'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 noBRCApathogenic 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)[ |
Cases: 2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers ofBRCA1pathogenic variants and 61 were carriers ofBRCA2pathogenic variants | Gleason 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 aBRCApathogenic 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 wereBRCA1/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)[ |
Cases: 4,187 men who underwent prostate biopsy for elevated PSA or abnormal exam, including 26 men with at least oneBRCAcoding pathogenic variant (all 26 codingexonsofBRCAwere sequenced forpolymorphisms) | Gleason score 7–10: | Cases median PSA: 56.3 | Not fully assessed in cases and controls | The 12-year survival for men with aBRCA2pathogenic variant was inferior to that of men without aBRCA2pathogenic variant (61.8% vs. 94.3%;P< 10−4). Among the men with high-grade disease (Gleason 7–9), the presence of aBRCA2pathogenic 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 noBRCAcoding pathogenic variants (all 26 coding exons ofBRCAwere sequenced for polymorphisms) | — Controls 54% | Controls median PSA: 13.3 |
Men harboring pathogenic variants in the United Kingdom and Ireland were prospectively followed for prostate cancer diagnoses (BRCA1 [n = 16/376] and BRCA2 [n = 26/447]; median follow-up, 5.9 y and 5.3 y, respectively).[
These studies suggest that prostate cancer in BRCA pathogenic variant carriers may be associated with aggressive disease features including a high Gleason score, a high prostate-specific antigen (PSA) level at diagnosis, and a high tumor stage and/or grade at diagnosis. This is a finding that warrants consideration when patients undergo cancer risk assessment and genetic counseling.[
BRCA1/BRCA2and 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.[
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)[ |
30 men diagnosed with prostate cancer who were carriers ofBRCA2999del5 founder pathogenic variants | 59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry theBRCA2999del5 pathogenic variant | BRCA2999del5 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)[ |
21 men diagnosed with prostate cancer who harbored aBRCA2pathogenic 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 ofBRCA2pathogenic 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)[ |
832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which 6 were carriers ofBRCA1pathogenic variants and 20 carriers ofBRCA2pathogenic variants | 454 AJ men with no history of cancer | After adjusting for stage, PSA, Gleason score, and therapy received: | Not assessed | TheBRCA15382insC founder pathogenic variant was not tested in this series |
– Carriers ofBRCA1 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 BRCA26174delT 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)[ |
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 noBRCApathogenic variant found in the family | BRCA2carriers 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 | BRCA2carriers 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 fewBRCA1carriers available to include in the analysis |
Castro et al. (2013)[ |
2,019 men diagnosed with prostate cancer from the UK, of whom 18 were carriers ofBRCA1pathogenic variants and 61 were carriers ofBRCA2pathogenic variants | 1,940 men who wereBRCA1/BRCA2noncarriers | 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)[ |
1,302 men from the UK with local or locally advanced prostate cancer, including 67 carriers ofBRCA1/BRCA2pathogenic variants | 1,235 men who wereBRCA1/BRCA2noncarriers | 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 theBRCAregion
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.[
Another study from the UM-PCGP examined common genetic variation in BRCA1.[
HOXB13
Key points
HOXB13 was the first gene found to be associated with hereditary prostate cancer. The HOXB13 G84E variant has been extensively studied because of its association with prostate cancer risk.
Background
Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[
Validation and confirmatory studies
A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[
Additional studies have emerged that better define the carrier frequency and prostate cancer risk associated with the HOXB13 G84E pathogenic variant.[
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.[
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).[
However, a 2018 publication of a study combining multiple prostate cancer cases and controls of Nordic origin along with functional analysis reported that simultaneous presence of HOXB13 (G84E) and CIP2A (R229Q) predisposes men to an increased risk of prostate cancer (OR, 21.1; P = .000024).[
HOXB13pathogenic variants in diverse populations
A study of Chinese men with and without prostate cancer failed to identify the HOXB13 G84E pathogenic variant; however, there was an excess of a novel variant, G135E, in cases compared with controls.[
Two studies confirmed the association between the HOXB13 X285K variant and increased prostate cancer risk in African American men after this variant was identified in Martinique.[
Penetrance
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.[
Biology
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 HOXB13 G84E or other pathogenic variants have yet to be defined.
DNA mismatch repair genes (Lynch syndrome)
Five genes are implicated in mismatch repair (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, duodenal cancers, and transitional cell cancers of the ureter and renal pelvis. For more information about other cancers that are associated with Lynch syndrome, see the Lynch syndrome section in Genetics of Colorectal Cancer. Reports have suggested that prostate cancer may be observed in men harboring an MMR gene pathogenic variant.[
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.[
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.[
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).[
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.[
EPCAM 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 the MSH2 gene) induce methylation of the MSH2 promoter, resulting in MSH2 protein loss.[
ATM
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurological deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygous carriers of ATM pathogenic variants.[
CHEK2
CHEK2 has also been investigated for a potential association with prostate cancer risk. For more information on other cancers associated with CHEK2 pathogenic variants, see the CHEK2 section in Genetics of Breast and Gynecologic Cancers and the CHEK2 section in Genetics of Colorectal Cancer. 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.[
TP53
TP53 has also been investigated for a potential association with prostate cancer risk. For more information about other cancers associated with TP53 pathogenic variants, see the Li-Fraumeni Syndrome section in Genetics of Breast and Gynecologic Cancers. 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.[
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.[
Further evidence supports an association between prostate cancer and germline TP53 pathogenic variants,[
NBN/NBS1
NBN, which is also known as NBS1, 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 an NBN pathogenic variant.[
Multigene testing studies in prostate cancer
Prevalence of pathogenic variants with prostate cancer risk on multigene panel testing
The following section gives information about additional genes that may be on hereditary prostate cancer 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.[
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.[
Germline pathogenic variants associated 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.[
Study | Cohort | Germline Results for Prostate Cancer | Comments | ||
---|---|---|---|---|---|
mCRPC = metastatic castration-resistant prostate cancer. | |||||
a Potential overlap of cohorts. | |||||
Robinson et al. (2015)a[ |
Whole-exomeand 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[ |
692 men with metastatic prostate cancer, unselected for family history; analysis focused on 20 genes involved in maintaining DNA integrity and associated withautosomal dominantcancer–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)[ |
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%) |
Common Risk Variants and Polygenic Risk Scores for Prostate Cancer
GWAS and SNPs
Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. However, when combined into a polygenic risk score (PRS), these confirmed genetic risk variants may prove to be useful for prostate cancer risk stratification and to identify men for targeted screening and early detection. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts. Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.
Beginning in 2006, multiple genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24.[
Since prostate cancer risk loci have been discovered at 8q24, more than 250 variants have been identified at other chromosomal risk loci. These chromosomal risk loci were detected by multistage GWAS, which were comprised of thousands of cases and controls and were validated in independent cohorts.[
Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNV frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[
The African American population is of particular interest because American men with West African ancestry are at higher risk of prostate cancer than any other group. A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry.[
Statistically well-powered GWAS have also been launched to examine inherited cancer risk in Japanese and Chinese populations. Investigators discovered that these populations share many risk regions observed in African American men.[
Polygenic risk scores for prostate cancer
Current GWAS findings account for an estimated 58% of disease risk that is heritable. About 6% of the familial RR of prostate cancer has been attributed to rare genetic variants.[
In a 2018 study, 147 GWAS variants known to be associated with prostate cancer were used to calculate a PRS for more than 140,000 men.[
The prostate cancer PRS's predictive value was maintained when it was applied to populations of men who carry deleterious variants in BRCA1 or BRCA2; this was particularly true among those in the top 95% distribution of the PRS.[
The Stockholm-3 Model (S3M) was developed on the basis of a study of 58,000 Swedish men aged 50 to 69 years. Men were genotyped for 233 prostate cancer risk–associated variants, and these data were used with other clinical data to risk-stratify men. Compared with PSA alone (area under the curve [AUC], 0.56), the addition of SNVs to clinical factors (S3M) improved prediction (AUC, 0.75) of clinically significant (i.e., Gleason score ≥7) prostate cancer.[
In 2021, a prospective study was done on participants from the U.K. Biobank. This cohort consisted of 208,685 men (mostly of European ancestry). Results suggested that prostate cancer risk–associated single nucleotide polymorphisms (SNPs) can provide useful information when they are added to an individual's family history and rare pathogenic variant status.[
Research focused on the associated risk of prostate cancer and the predictability of PRSs is ongoing.[
As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful. Finally, GWAS are providing more insight into the mechanism of prostate cancer risk. It is now apparent that a large proportion of risk variants affect the activity of regulatory elements and, in turn, distal genes.[
Germline SNPs 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 regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess these associations prospectively.
References:
This section addresses the impact of genetics on prostate cancer screening, surveillance, and treatment. For more information about prostate cancer screening, surveillance, and treatment, see Prostate Cancer Screening and Prostate Cancer Treatment.
Prostate Cancer Screening
Background
Decisions about risk-reducing interventions for patients with an inherited predisposition to prostate cancer, as with any disease, are best guided by randomized controlled clinical trials and knowledge of the underlying natural history of the process. However, existing studies of screening for prostate cancer in high-risk men (men with a positive family history of prostate cancer and African American men) are predominantly based on retrospective case series or retrospective cohort analyses. Because awareness of a positive family history can lead to more frequent work-ups for cancer and result in apparently earlier prostate cancer detection, assessments of disease progression rates and survival after diagnosis are subject to selection, lead time, and length biases. This section focuses on screening and risk reduction of prostate cancer among men predisposed to the disease; data relevant to screening in high-risk men are primarily extracted from studies performed in the general population.
Screening
Information is limited about the efficacy of commonly available screening tests such as the digital rectal exam (DRE) and serum prostate-specific antigen (PSA) in men genetically predisposed to developing prostate cancer. Furthermore, comparing the results of studies that have examined the efficacy of screening for prostate cancer is difficult because studies vary with regard to the cutoff values chosen for an elevated PSA test. For a given sensitivity and specificity of a screening test, the positive predictive value (PPV) increases as the underlying prevalence of disease rises. Therefore, it is theoretically possible that the PPV and diagnostic yield will be higher for the DRE and for PSA in men with a genetic predisposition than in average-risk populations.[
Most retrospective analyses of prostate cancer screening cohorts have reported PPV for PSA, with or without DRE, among high-risk men in the range of 23% to 75%.[
| Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2020)[ |
Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 2.2024)[ |
NCCN Prostate Cancer Early Detection (Version 2.2023)a[ |
---|---|---|---|
NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen. | |||
a Forgermline pathogenic variantsother thanBRCA2(includingATMand Lynch syndromegenes), it is reasonable to consider beginning shared decision-making about PSA screening at age 40 years and to consider screening at annual intervals, rather than every other year. | |||
Screening in BRCA1Carriers | Consider baseline PSA for age >40 y or 10 years before the earliest prostate cancer diagnosis in the family | Consider prostate cancer screening starting at age 40 y | Consider beginning shared decision-making about PSA screening at age 40 y |
NCCN Genetic/Familial High-Risk Assessment guidelines suggest that individuals see the NCCN Prostate Cancer Early Detection guidelines for guidance on prostate cancer screening intervals[ |
Consider annual screening rather than screening every other year | ||
Screening in BRCA2 Carriers | Recommend baseline PSA for age >40 y or 10 years before the earliest prostate cancer diagnosis in the family | Recommend prostate cancer screening starting at age 40 y | Recommend PSA screening starting at age 40 y |
Screening interval determined by baseline PSA level | NCCN Genetic/Familial High-Risk Assessment guidelines suggest that individuals see the NCCN Prostate Cancer Early Detection guidelines for guidance on prostate cancer screening intervals[ |
Consider annual screening rather than screening every other year | |
Screening in HOXB13 Carriers | Baseline PSA for age >40 y or 10 years before the earliest prostate cancer diagnosis in the family | None provided | Consider beginning shared decision-making about PSA screening at age 40 y |
Screening interval determined by baseline PSA level | Consider annual screening rather than screening every other year |
Screening Recommendation Source | Population | Test | Age Screening Initiated | Frequency | Comments |
---|---|---|---|---|---|
DRE = digital rectal exam; FDR = first-degree relative; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen; SDR =second-degree relative. | |||||
a DRE is recommended in addition to PSA test for men with hypogonadism. | |||||
b A suspicious family history includes, but is not limited to, an FDR or SDR with metastatic prostate cancer, ovarian cancer, male breast cancer, female breast cancer at age ≤45 y, colorectal or endometrial cancer at age ≤50 y, or pancreatic cancer; this may also include two or more FDRs or SDRs with breast, prostate (excluding clinically localized Grade Group 1 disease), colorectal, or endometrial cancer at any age. | |||||
United States Preventive Services Task Force (2018)[ |
Men aged 55–69 y | PSA | N/A | N/A | In determining whether PSA-based screening is appropriate in individual cases, patients and clinicians should consider the benefits and harms of PSA screening based on family history, race and ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs |
American Urological Association (2023)[ |
African American men, men with germline pathogenic variants in hereditary prostate cancer genes, and men with strong family histories of prostate cancer | PSA | 40 to 45 y | Screening is individualized based on the patient's personal preferences and an informed discussion regarding the uncertainty of benefit and associated harms | |
American Cancer Society (2023)[ |
African American men | PSA with or without DREa | ≥45 y | Screen every 2 y if PSA is <2.5 ng/mL; screen annually if PSA level is ≥2.5 ng/mL; if PSA levels are between 2.5–4.0 ng/mL, an individualized risk assessment can be performed, which incorporates other prostate cancer risk factors (particularly for high-grade cancer, which may be used for a referral recommendation) | Counseling consists of a review of the benefits and limitations of testing so that a clinician-assisted, informed decision about testing can be made. It is recommended that prostate cancer screening be accompanied by an informed decision-making process |
Men with an FDR who was diagnosed with prostate cancer at <65 y | PSA with or without DREa | ≥45 y | |||
Men with multiple FDRs who were diagnosed with prostate cancer at <65 y | PSA with or without DREa | ≥40 y | |||
NCCN Prostate Cancer Early Detection (Version 2.2023)[ |
African American men | Baseline PSA | 40 y | Consider screening at annual intervals rather than every other year | The panel states that it is reasonable for African American men to consider beginning shared decision-making about PSA screening with their providers at age 40 y |
Men with a suspicious family historyb | Baseline PSA | 40 y | Screen every 2–4 y if PSA level <1 ng/mL, DRE normal; if the family history is concerning, NCCN recommends shared decision-making to determine the frequency of PSA screening | Referral to a cancer genetics professional is recommended for those with a known or suspected pathogenic variant in a cancersusceptibility gene [ |
|
Screen every 1–2 y if PSA level ≤3 ng/mL, DRE normal (if done) |
Level of evidence: 5
Screening in carriers ofBRCApathogenic variants
IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer) is an international study focused on prostate cancer screening in carriers of BRCA1/BRCA2 pathogenic variants versus noncarriers.[
Interim results from the IMPACT study (now comprising 2,932 participants including 919 BRCA1 carriers and 902 BRCA2 carriers) demonstrated a cancer incidence rate (per 1,000 person-years) that was higher in BRCA2 carriers compared with noncarriers (19 vs. 12; P = .03). There was no statistical difference in the cancer incidence rates between BRCA1 carriers and noncarriers. Cancer in BRCA2 carriers, but not in BRCA1 carriers, was diagnosed at an earlier age and was more likely to be clinically significant.[
Level of evidence (screening in carriers of BRCA pathogenic variants): 3
Impact of Germline Genetics on Management and Treatment of Metastatic Prostate Cancer
Targeted therapies on the basis of genetic results are increasingly driving options and strategies for treatment in oncology. These therapeutic approaches include candidacy for targeted therapy (such as poly [ADP-ribose] polymerase [PARP] inhibitors or immune checkpoint inhibitors), use of platinum-based chemotherapy, and sequencing of androgen-signaling therapy versus chemotherapy. Multiple genetically informed clinical trials are under way for men with prostate cancer.[
Study | Cohort | Germline Results | Intervention | Outcomes and Comments | |
---|---|---|---|---|---|
ADT = androgen deprivation therapy; AR = androgen receptor; CI = confidence interval; CSS = cause-specific survival; DDR = DNA damage repair; FDA = U.S. Food and Drug Administration; HR = hazard ratio; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; mPC = metastatic prostate cancer; ORR = objective response rate; OS = overall survival; PARP = poly (ADP-ribose) polymerase; PC = prostate cancer; PFS = progression-free survival; PSA = prostate-specific antigen; RR = relative risk. | |||||
a This study reported both germline and somatic genetic test results. | |||||
Retrospective | |||||
Annala et al. (2017)[ |
319 men with mCRPC; performed germline sequencing of 22 DNA repair genes; all participants previously received ADT and their PCs progressed | 24/319 (7.5%) had DDR germline pathogenic variants: | Patientswith mCRPC and a germline pathogenic variant received the following as a first-line AR-targeted therapy: docetaxel/cabazitaxel (41%), enzalutamide (23%), or abiraterone (36%) | Patients with DNA repair defects had decreased responses to ADT: | |
—BRCA2: 16/319 (5.0%) | |||||
—ATM: 1/319 (0.3%) | — Time from ADT initiation to mCRPC: Germline positive, 11.8 mo (n = 22) vs. germline negative, 19.0 mo (n = 113) (P = .031) | ||||
—BRCA1: 1/319 (0.3%) | Patients with mCRPC butwithout a germline pathogenic variant received the following as a first-line AR-targeted therapy: docetaxel/cabazitaxel (33%), enzalutamide (18%), abiraterone (39%), or other (10%) | ||||
—PALB2: 2/319 (0.6%) | — PFS on first-line AR-targeted therapy: Germline positive, 3.3 mo vs. germline negative, 6.2 mo (P = .01) | ||||
Pomerantz et al. (2017)[ |
141 men with mCRPC treated with docetaxel | 8/141 (5.7%) hadBRCA2germline pathogenic variants | Patients received at least two doses of carboplatin and docetaxel | 6/8 men withBRCA2germline pathogenic variants (75%) had PSA levels that declined by 50% vs. 23/133 in men withoutBRCA2germline pathogenic variants (17%) (P< .001) | |
A small case series (n = 3) showed a response to platinum chemotherapy with biallelic inactivation ofBRCA2, defined as either biallelic somaticBRCA2pathogenic variants or a germline pathogenic variant plus a somaticBRCA2pathogenic variant[ |
|||||
Mateo et al. (2018)[ |
390 men with mPC; retrospective review | 60/390 (15.4%) had DDR germline pathogenic variants: | Patients received abiraterone, enzalutamide, and docetaxel; an exploratory subgroup analysis was done for PARP inhibitors/platinum chemotherapy | 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 PC (61% in carriers vs. 54% in noncarriers) | ||||
— Median PFS on first-line abiraterone/enzalutamide (8.3 mo in both carriers and noncarriers) | |||||
— RR of PC on first-line abiraterone/enzalutamide (46% in carriers vs. 56% in noncarriers) | |||||
Carter et al. (2019)[ |
1,211 men with PC on active surveillance | 2.1% of patients had germline pathogenic variants inBRCA1/BRCA2/ATM | Patients were put on active surveillance | 289 patients had their PC tumor grades reclassified: 11/26 patients had pathogenic variants inBRCA1/BRCA2/ATMand 278/1,185 patients did not have a pathogenic variant inBRCA1/BRCA2/ATM(noncarriers); adjusted HR, 1.96 (95% CI, 1.004–3.84;P = .04) | |
Tumor reclassification occurred in 6/11BRCA2carriers and 283/1,200 noncarriers; adjusted HR, 2.74 (95% CI, 1.26–5.96;P = .01) | |||||
Of the men who had their PCs reclassified, 3.8% had aBRCA1,BRCA2, orATMpathogenic variant, and 2.1% only had aBRCA2 pathogenic variant. Of the men whose PCs were not reclassified, 1.6% had aBRCA1,BRCA2, orATMpathogenic variant, and 0.5% only had aBRCA2 pathogenic variant. TheP value forBRCA1/BRCA2/ATMcarriers with PCs reclassified versus those without PCs reclassified was .04. TheP value forBRCA2carriers with PCs reclassified versus those without PCs reclassified was .03 | |||||
Marshall et al. (2019)[ |
46 men with mCRPC were offered olaparib; 23 men had germline pathogenic variants (13 men were not tested) | 23 men had germline pathogenic variants inBRCA1/BRCA2/ATM; 2 men hadBRCA1pathogenic variants, 15 men hadBRCA2 pathogenic variants, and 6 men hadATMpathogenic variants | Patients received olaparib | When patients were given olaparib, PSA levels were reduced by 50% in 13/17 (76%) men withBRCA1/BRCA2pathogenic variants and in 0/6 (0%) men withATMpathogenic variants (Fisher's exact test;P = .002) | |
Patients withBRCA1/BRCA2 pathogenic variants had a median PFS of 12.3 mo, while patients withATMpathogenic variants had a median PFS of 2.4 mo (HR, 0.17; 95% CI, 0.05–0.57;P = .004) | |||||
Sokolova et al. (2021)[ |
90 men with PC; 76/90 had metastatic disease when their PC was diagnosed; participants were matched for PC stage and year of germline testing; participants had similar ages, Gleason grades, and PSA levels at diagnosis | 45 men withATMgermline pathogenic variants; 45 men withBRCA2 germline pathogenic variants | Patients received various systemic therapies | No changes were observed when different groups were given abiraterone, enzalutamide, or docetaxel | |
When patients were given PARP inhibitors, PSA levels were reduced by 50% in 0/7 men withATMgermline pathogenic variants and in 12/14 men withBRCA2germline pathogenic variants (P< .001); this response was significant | |||||
Study limitations included the following: retrospective study, no zygosity data | |||||
Prospective | |||||
Antonarakis et al. (2018)[ |
172 men with mCRPC began treatment with abiraterone or enzalutamide | 22/172 (12.8%) had DDR germline pathogenic variants: | Patients received first-line hormonal therapy (abiraterone or enzalutamide) | In propensity score–weighted multivariable analyses, outcomes were superior in men with germlineBRCA1/BRCA2/ATMvariants 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/ATMgermline variants (P> .10) | |
—BRCA1/BRCA2/ATM: 9/172 (5.2%) | Study limitations included the following: only 9 patients withBRCA1/BRCA2/ATMpathogenic variants | ||||
Castro et al. (2019)[ |
419 men with mCRPC were enrolled when they were diagnosed with mPC | 68/419 (16.2%) had DDR germline pathogenic variants: | Patients received an androgen-signaling inhibitor (abiraterone or enzalutamide) as a first-line therapy and a taxane (docetaxel was given in 96.3% of patients) as a second-line therapyor patients received a taxane as a first-line therapy and an androgen-signaling inhibitor (abiraterone or enzalutamide) as a second-line therapy | CSS betweenATM/BRCA1/BRCA2/PALB2carriers and noncarriers was not statistically significant (23.3 mo vs. 33.2 mo;P = .264) | |
—BRCA2: 14/419 (3.3%) | |||||
—ATM: 8/419 (1.9%) | CSS was halved inBRCA2carriers (17.4 mo vs. 33.2 mo;P = .027), andBRCA2pathogenic variants were identified as an independent prognostic factor for CSS (HR, 2.11;P = .033) | ||||
—BRCA1: 4/419 (1%) | Significant interactions betweenBRCA2status and treatment type (androgen-signaling inhibitor vs. taxane therapy) were observed (CSS-adjustedP = .014; PFS-adjustedP = .005) | ||||
—PALB2: None | CSS (24.0 mo vs. 17.0 mo) and PFS (18.9 mo vs. 8.6 mo) were greater inBRCA2carriers treated with first-line abiraterone or enzalutamide when compared with first-line taxanes | ||||
de Bono et al. (2020)[ |
387 men in the PROfound study who had mCRPC with disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone) | Currently, the FDA has approved olaparib for use in patients with mCRPC who have a somatic or germline pathogenic variant in an HRR gene. The PROfound study cited data fromMateo et al. 2015, which discovered that about half of the HRR gene variants in patient tumors were germline in nature. Results in this study reported on olaparib response in individuals with somatic variants. Data on germline pathogenic variants will be reported in the future | Randomized, open-label, phase III trial in which patients received olaparib (300 mg twice per day)or the physician's choice of enzalutamide (160 mg once per day) or abiraterone (1,000 mg once per day) plus prednisone (5 mg twice per day) | In cohort A, imaging-based PFS was significantly longer in the olaparib group than in the control group (median, 7.4 mo vs. 3.6 mo; HR for progression or death, 0.34; 95% CI, 0.25–0.47;P< .001). The median OS in cohort A was 18.5 mo in the olaparib group and 15.1 mo in the control group; 81% of the patients in the control group who had disease progression crossed over to receive olaparib | |
Cohort A: 245 men with >1 somatic variant inBRCA1,BRCA2, orATM | |||||
Cohort B: 142 men with >1 somatic variant in any of the following genes:BRIP1,BARD1,CDK12,CHEK1,CHEK2,FANCL,PALB2,PPP2R2A,RAD51B,RAD51C,RAD51D, orRAD54L | |||||
Hussain et al. (2020)[ |
387 men with mCRPC in the PROfound study; PC progressed when taking enzalutamide, abiraterone, or both | Currently, the FDA has approved olaparib for use in patients with mCRPC who have a somatic or germline pathogenic variant in an HRR gene. The PROfound study cited data fromMateo et al. 2015, which discovered that about half of the HRR gene variants in patient tumors were germline in nature. Results in this study reported on olaparib response in individuals with somatic variants. Data on germline pathogenic variants will be reported in the future | Patients received treatment that was randomly assigned in a 2:1 ratio for olaparib versus control therapy; control therapy consisted of the provider's choice of enzalutamide or abiraterone, plus prednisone. Crossover to olaparib was permitted when PC progressed on imaging | The median OS in cohort A was 19.1 mo with olaparib and 14.7 mo with control therapy. The HR for death (adjusted for crossover from control therapy) was 0.42 (95% CI, 0.19–0.91) | |
Cohort A: 245 men with >1 somatic variant inBRCA1,BRCA2, orATM | The median OS in cohort B was 14.1 mo for olaparib and 11.5 mo for control therapy. The HR for death (adjusted for crossover from control therapy) was 0.83 (95% CI, 0.11–5.98) | ||||
Cohort B: 142 men with >1 somatic variant in any of the following genes:BRIP1,BARD1,CDK12,CHEK1,CHEK2,FANCL,PALB2,PPP2R2A,RAD51B,RAD51C,RAD51D, orRAD54L | |||||
Abida et al. (2020)a[ |
115 men with mCRPC from the TRITON2 study with a deleterious somatic or germline pathogenic variant inBRCA1/BRCA2; patients had mCRPCs that progressed after treatment with one to two lines of next-generation AR-directed therapy and one taxane-based chemotherapy | 44/115 (38%) hadBRCA1/BRCA2germline pathogenic variants: | Patients received one or more doses of rucaparib (600 mg) | The ORR was 43.5% in men with measurable disease and 50.8% in men without measurable disease. ORRs were similar for men with germline and somatic variants and for men withBRCA1/BRCA2pathogenic variants | |
—BRCA1: 5/115 (4%) | |||||
—BRCA2: 39/115 (34%) | |||||
71/115 (62%) hadBRCA1/BRCA2somatic variants: | 63/115 men had a confirmed PSA response (54.8%), which differed by gene; however, theBRCA1group was small: | ||||
—BRCA1: 8/115 (7%) | — BRCA1: 2/13 (15.4%) | ||||
—BRCA2: 63/115 (55%) | —BRCA2: 61/102 (59.8%) | ||||
De Bono et al. (2021)a[ |
104 men with progressive mCRPC and pathogenic variants in DDR-HRR genes; patients received at least one dose of talazoparib | 25/71 (25%) patients had germline pathogenic variants: 13 inBRCA2, 4 inATM, and 8 in other genes | Patients received one or more doses of talazoparib per day (received 1 mg per day or 0.75 mg per day if the patient had moderate renal impairment) | The ORR was observed in 7/28 (25%) men with germline pathogenic variants | |
Patients also had somatic variants in the following genes: 61 inBRCA1/2, 57 inBRCA2, 4 inPALB2, 17 inATM, 22 in other genes (ATR,CHEK2,FANCA,MLH1,MRE11A,NBN, andRAD51C) | After a median follow-up period of 16.4 mo (range, 11.1–22.1), the ORR for patients with somatic variants was 29.8% (31 of 104 patients; 95% CI, 21.2%–39.6%). Clinical benefit (defined as patients with complete response, partial response, or stable disease for ≥6 months from treatment start) varied between individuals with different pathogenic variants:BRCA1/2(56%),BRCA2(56%),PALB2(25%),ATM(24%), other (0%) |
References:
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