Prostate cancer is highly heritable. Up to 60% of prostate cancer risk is caused by inherited factors. The inherited risk is comprised of risk from common genetic variants and risk from pathogenic variants in moderate-risk and high-risk genes. As with breast and colon cancers, familial clustering of prostate cancer has been reported frequently.

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. Recommendations and guidelines for genetic counseling referrals are based on an individual's age at prostate cancer diagnosis, prostate cancer stage at diagnosis, and specific patterns of cancer in the family history. However, uptake of genetic testing based on an individual's family history of prostate cancer and/or a diagnosis of prostate cancer is variably implemented across practice settings and geographical regions.

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. Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer diagnosis rates are increasing, and there is evidence that cases may be more aggressive in this subpopulation.

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:

• White: 103.5 cases/100,000 men.
• Asian or Pacific Islander: 57.2 cases/100,000 men.
• American Indian or Alaska Native: 82.6 cases/100,000 men.
• Hispanic or Latino: 87.2 cases/100,000 men.

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:

• White: 17.8/100,000 men.
• Asian or Pacific Islander: 8.6/100,000 men.
• American Indian or Alaska Native: 21.9/100,000 men.
• Hispanic or Latino: 15.3/100,000 men.

Globally, prostate cancer incidence and mortality rates also vary widely from country to country. The etiology of this variation in prostate cancer risk is likely multifactorial and may be due to biological factors, access to health care, and other social determinants of health.

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 family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative. Risk is increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years.

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).

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. This is consistent with findings from previous cohorts, though, notably, not all series have detected this association. The HPFS and other studies have also shown that men with a family history of both prostate and breast/ovarian cancers were at an even higher risk of prostate cancer compared with men with a family history of either prostate or breast/ovarian cancer alone. A proportion of the increased prostate cancer risk associated with family history of breast cancer is likely due to pathogenic variants in the DNA damage repair pathway, most commonly BRCA2. For more information, see the BRCA1 and BRCA2 section. The association between prostate and breast cancers in families appears bidirectional. Among women, a family history of prostate cancer is likewise associated with increased risk of breast 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. One study reported an approximately twofold increased risk of prostate cancer among first- and second-degree relatives of probands with colorectal cancer meeting Amsterdam I or Amsterdam II criteria for Lynch syndrome. For more information on Amsterdam criteria, see the Defining Lynch syndrome families section in Genetics of Colorectal 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), 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian American individuals than among African American or White individuals. A positive family history was associated with a twofold to threefold increase in relative risk (RR) in each of the three ethnic groups. The overall odds ratio (OR) associated with a family history of prostate cancer was 2.5 (95% confidence interval , 1.9–3.3) with adjustment for age and ethnicity.

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 ), 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. A large population-based study from Utah reported that men with either of the following were at an increased risk for early-onset prostate cancer: 1) three or more FDRs diagnosed with prostate cancer, or 2) two or more FDRs or second-degree relatives with prostate cancer.

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. Prostate cancer heritability (when considering low, moderate, and high-penetrant genetic factors) can be as high 57% (95% CI, 51%–63%). Genetic variants that contribute to this risk are continuously being identified. Prostate cancer heritability rates may also vary in different racial and ethnic populations. For more information, see the Germline Genetics for Prostate Cancer section.

Risk assessment for prostate cancer primarily involves the intake of a patient's family cancer history. Family history intake includes the following:

• Information about cancers* in male and female blood relatives on maternal and paternal sides of the family.
• Ages at cancer diagnoses.
• Ages of death from cancer.
• The number of relatives with metastatic prostate cancer.
• The number of relatives who died of prostate cancer.
• Information on relatives who are undergoing cancer screening, if known.

*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). Black men also have more than twice the rate of prostate cancer–specific death (37.5 deaths/100,000 men) than White men (17.8 deaths/100,000 men). This increased prostate cancer risk may be due to challenges, including the following: 1) access to care, 2) limited awareness of prostate cancer screening programs, 3) limited engagement in prostate cancer screening/genetic testing, and 4) the presence of specific genetic markers that can increase prostate cancer risk.

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:

• Hereditary breast and ovarian cancer syndrome: Family members with ovarian cancer, pancreatic cancer, metastatic/high-risk prostate cancer, male breast cancer, and/or breast cancer diagnosed at or before age 50 years.
• Lynch syndrome: Family members with colorectal or endometrial cancer diagnosed at or before age 50 years, ovarian cancer, pancreatic cancer, urothelial cancer, and/or upper GI cancer.
• Hereditary prostate cancer: Multiple generations with prostate cancer, deaths from prostate cancer, and/or family members with metastatic prostate cancer.

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.

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. Hereditary prostate cancer genetic testing criteria are based on an individual's family history, personal/disease characteristics, and tumor sequencing results. The genes recommended for genetic testing vary based on national guidelines and consensus conference recommendations. Precision therapy has emerged as a major driver for germline genetic testing and may be a separate reason to pursue testing beyond the criteria stated in Table 2. The National Comprehensive Cancer Network (NCCN) Prostate Cancer guidelines recommend testing for at least BRCA1, BRCA2, ATM, CHEK2, PALB2, HOXB13,MLH1, MSH2, MSH6, and PMS2 for men meeting specific testing indications. A consensus conference in 2019 addressed the role of genetic testing for inherited prostate cancer. Family history–based indications for genetic testing included testing for BRCA1/BRCA2, HOXB13, DNA mismatch repair (MMR) genes, and ATM. Tumor sequencing that identifies variants that may be germline in origin, like variants in BRCA1/BRCA2, DNA MMR genes, or ATM and other genes, warrants confirmatory germline testing. Somatic findings for which germline testing is considered include the following:

• Somatic mutations that are associated with germline susceptibility.
• Hypermutated tumors, which are indicative of DNA MMR.
• Chromosome rearrangements in specific tumors.
• High-variant allele frequency (percent of sequence reads that have the identified variant). Variant allele frequency can be altered for reasons not associated with germline variants such as loss of heterozygosity, ploidy (copy number variants), tumor heterogeneity, and tumor sample purity.

Table 2. Indications for Prostate Cancer Genetic Testing

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

BRCA1 and BRCA2

Studies of male carriers of BRCA1 and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers. Prostate cancer, in particular, has been observed at higher rates in male carriers of BRCA2 pathogenic variants than in the general population. For more information about BRCA1 and BRCA2 pathogenic variants, see BRCA1 and BRCA2: Cancer Risks and Management.

BRCA–associated prostate cancer risk

The risk of prostate cancer in carriers of BRCA pathogenic variants has been studied in various settings.

In an effort to clarify the relationship between BRCA pathogenic variants and prostate cancer risk, findings from several case series are summarized in Table 3.

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

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 , 2.64; 95% confidence interval , 2.03–3.47) than in BRCA1 carriers (OR, 1.35; 95% CI, 1.03–1.76). Several studies cited in Table 3 were included in this meta-analysis.

Prevalence of BRCA founder pathogenic variants in men with prostate cancer

Ashkenazi Jewish population

Several studies in Israel and in North America have analyzed the frequency of BRCA founder pathogenic variants among Ashkenazi Jewish (AJ) men with prostate cancer. Two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic variant (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these pathogenic variants in the general Jewish population are 0.9% (95% 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. In these studies, the relative risks (RRs) were commonly greater than 1, but only a few were statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder pathogenic variants.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia area who carried one of the BRCA Ashkenazi founder pathogenic variants. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4%–30%) among carriers of the founder pathogenic variants and 3.8% (95% CI, 3.3%–4.4%) among noncarriers. 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 ).

The studies summarized in Table 4 used similar case-control methods to examine the prevalence of Ashkenazi founder pathogenic variants among Jewish men with prostate cancer and found an overall positive association between carrier status of founder pathogenic variants and prostate cancer risk.

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

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.

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

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). These observations might explain some of the inconsistencies encountered in prior studies of these associations, because varied populations may have differences in the proportion of individuals with specific BRCA1/BRCA2 pathogenic variants.

Several case series have also explored the role of BRCA1 and BRCA2 pathogenic variants and prostate cancer risk.

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

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 of BRCA pathogenic variants

The studies summarized in Table 7 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 pathogenic variant.

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

Men harboring pathogenic variants in the United Kingdom and Ireland were prospectively followed for prostate cancer diagnoses (BRCA1 and BRCA2 ; median follow-up, 5.9 y and 5.3 y, respectively). The prostate cancers identified covered the spectrum of Gleason scores from less than 6 to greater than 8; however, they differed by gene:

• BRCA1 Gleason score less than 6; standardized incidence ratio (SIR), 3.50 (95% CI, 1.67–7.35) and Gleason score greater than 7; SIR, 1.80 (95% CI, 0.89–3.65).
• BRCA2 Gleason score less than 6; SIR, 3.03 (95% CI, 1.24–7.44) and Gleason score greater than 7; SIR, 5.07 (95% CI, 3.20–8.02).

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. Research is under way to gain insight into the biological 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.

BRCA1/BRCA2 and survival outcomes

Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 pathogenic variants have been examined for survival. In an unadjusted analysis performed on a case series, median survival was 4 years in 183 men with prostate cancer with a BRCA2 pathogenic variant and 8 years in 119 men with a BRCA1 pathogenic variant. The study suggests that carriers of BRCA2 pathogenic variants have a poorer survival than carriers of BRCA1 pathogenic variants. The case-control studies summarized in Table 8 further assess this observation.

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

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. 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. Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancers was found to have a truncating pathogenic variant (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence of a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating variants in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.

Another study from the UM-PCGP examined common genetic variation in BRCA1. 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 variants (SNVs) tagging common haplotype variation in a 200-kb region surrounding and including BRCA1. Three SNVs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNV rs1799950 (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, SNV rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.

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.

• Overall risk of prostate cancer with the G84E variant ranges from 3- to 5-fold, with a higher risk of early-onset prostate cancer with the G84E variant of up to 10-fold.
• Penetrance for carriers of the G84E variant is an approximate 60% lifetime risk of prostate cancer by age 80 years.
• There is no clear association of the G84E variant with aggressive prostate cancer or other cancers.
• Preliminary studies suggest additional variants in HOXB13 may be relevant for prostate cancer risk in diverse populations.

Background

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer. Fine-mapping of this region provided strong evidence of linkage (LOD score, 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger. The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins University). Probands from four families were discovered to have a recurrent pathogenic variant (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the pathogenic variant. The pathogenic variant status was determined in 5,083 additional cases and 2,662 controls. Carrier frequencies and ORs for prostate cancer risk were as follows:

• Men with a positive family history of prostate cancer, 2.2% versus negative, 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10-4).
• Men younger than 55 years at diagnosis, 2.2% versus older than 55 years, 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10-4).
• Men with a positive family history of prostate cancer and younger than 55 years at diagnosis, 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years, 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10-6).
• Men with a positive family history of prostate cancer and older than 55 years at diagnosis, 1.2%.
• Controls, 0.1% to 0.2%.

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. Within carrier families, the G84E pathogenic variant was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E pathogenic variant was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10-6).

Additional studies have emerged that better define the carrier frequency and prostate cancer risk associated with the HOXB13 G84E pathogenic variant. This pathogenic variant appears to be restricted to White men, primarily of European descent. The highest carrier frequency of 6.25% was reported in Finnish early-onset cases. A pooled analysis of European Americans that included 9,016 cases and 9,678 controls found an overall G84E pathogenic variant frequency of 1.34% among cases and 0.28% among controls.

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. A pooled analysis reported a prostate cancer OR of 4.86 (95% CI, 3.18–7.69; P = 3.48 × 10-17) in men with HOXB13 pathogenic variants compared with noncarriers; this increased to an OR of 8.41 (95% CI, 5.27–13.76; P = 2.72 ×10-22) among men diagnosed with prostate cancer at age 55 years or younger. The OR was 7.19 (95% CI, 4.55–11.67; P = 9.3 × 10-21) among men with a positive family history of prostate cancer and 3.09 (95% CI, 1.83–5.23; P = 6.26 × 10-6) among men with a negative family history of prostate cancer. A meta-analysis that included 24,213 cases and 73,631 controls of European descent revealed an overall OR for prostate cancer by carrier status of 4.07 (95% CI, 3.05–5.45; P .00001). Risk of prostate cancer varied by geographical region: United States (OR, 5.10; 95% CI, 3.21–8.10; P .00001), Canada (OR, 5.80; 95% CI, 1.27–26.51; P = .02), Northern Europe (OR, 3.61; 95% CI, 2.81–4.64; P .00001), and Western Europe (OR, 8.47; 95% CI, 3.68–19.48; P .00001). In addition, the association between the G84E pathogenic variant and prostate cancer risk was higher for early-onset cases (OR, 10.11; 95% CI, 5.97–17.12). There was no significant association with aggressive disease in the meta-analysis.

Another meta-analysis that included 11 case-control studies also reported higher risk estimates for prostate cancer in HOXB13 G84E carriers (OR, 4.51; 95% CI, 3.28–6.20; P .00001) and found a stronger association between HOXB13 G84E and early-onset disease (OR, 9.73; 95% CI, 6.57–14.39; P .00001). An additional meta-analysis of 25 studies that included 51,390 cases and 93,867 controls revealed an OR for prostate cancer of 3.248 (95% CI, 2.121–3.888). The association was most significant in White individuals (OR, 2.673; 95% CI, 1.920–3.720), especially those of European descent. No association was found for breast or colorectal cancer. One population-based, case-control study from the United States confirmed the association of the G84E pathogenic variant with prostate cancer (OR, 3.30; 95% CI, 1.21–8.96) and reported a suggestive association with aggressive disease. In addition, one study identified no men of AJ ancestry who carried the G84E pathogenic variant. A case-control study from the United Kingdom that included 8,652 cases and 5,252 controls also confirmed the association of HOXB13 G84E with prostate cancer (OR, 2.93; 95% CI, 1.94–4.59; P = 6.27 × 10-8). The risk was higher among men with a family history of the disease (OR, 4.53; 95% CI, 2.86–7.34; P = 3.1 × 10−8) and in early-onset prostate cancer (diagnosed at age 55 y or younger) (OR, 3.11; 95% CI, 1.98–5.00; P = 6.1 × 10−7). No association was found between carrier status and Gleason score, cancer stage, OS, or cancer-specific survival.

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). Furthermore, dual carriers had elevated risk for high Gleason score (OR, 2.3; P = .025) and worse prostate cancer–specific survival (hazard ratio , 3.9; P = .048). Clinical validation is needed.

HOXB13 pathogenic 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. A large study of approximately 20,000 Japanese men with and without prostate cancer identified another novel HOXB13 variant, G132E, which was associated with prostate cancer with an OR of 6.08 (95% CI, 3.39–11.59).

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. One of these was a single-institution study, which sequenced HOXB13 in a clinical patient population of 1,048 African American men undergoing prostatectomy for prostate cancer. The HOXB13 X285K variant was identified in eight patients. In a case–case analysis, X285K variant carriers were at increased risk of developing clinically significant prostate cancer (1.2% X285K carrier rate in prostate cancers with a Gleason score ≥7 vs. 0% X285K carrier rate in prostate cancers with Gleason score 7; P = .028). Similarly, X285K variant carriers also had an increased chance of developing prostate cancer at an early age (2.4% X285K carrier rate in patients 50 years vs. 0.5% X285K carrier rate in patients ≥50 years; OR, 5.25; 95% CI, 1.00–28.52; P = .03). A second study included 11,688 prostate cancer cases and 10,673 controls from multiple large consortia. The HOXB13 X285K variant was only present in men of West African ancestry and was associated with a 2.4-fold increased chance of developing prostate cancer (95% CI, 1.5–3.9; P = 2 x 10-4). Individuals with the X285K variant were also more likely to have aggressive and advanced prostate cancer (Gleason score ≥8: OR, 4.7; 95% CI, 2.3–9.5; P = 2 x 10-5; stage T3/T4: OR, 4.5; 95% CI, 2.0–10.0; P = 2 x 10-4; metastatic disease: OR, 5.1; 95% CI, 1.9–13.7; P = .001). This information is important to consider when developing genetic tests for HOXB13 pathogenic variants in broader populations.

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. Another study from Australia reported an age-specific cumulative risk of prostate cancer of up to 60% by age 80 years. A study in the United Kingdom that included HOXB13 genotype data from nearly 12,000 men with prostate cancer enrolled between 1993 and 2014 reported that the average predicted risk of prostate cancer by age 85 years is 62% (95% CI, 47%–76%) for carriers of the G84E pathogenic variant. The risk of developing prostate cancer in variant carriers increased if the men had affected family members, especially those diagnosed at an early age.

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. The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male carriers of MMR gene pathogenic variants or obligate carriers. The expected number of cases among these 106 men was 1.52 (P .01); the men were younger at the time of diagnosis (60.4 y vs. 66.6 y; P = .006) and had more evidence of Gleason score of 8 to 10 (P .00001) than the cases from the Norwegian Cancer Registry. Kaplan-Meier analysis revealed that the cumulative risk of prostate cancer diagnosis by age 70 years was 30% in carriers of MMR gene pathogenic variants and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNVs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer. To assess the contribution of prostate cancer as a feature of Lynch syndrome, one study performed microsatellite instability (MSI) testing on prostate cancer tissue blocks from families enrolled in a prostate cancer family registry who also reported a history of colon cancer. Among 35 tissue blocks from 31 distinct families, two tumors from families with MMR gene pathogenic variants were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer. Other studies are attempting to characterize rates of prostate cancer in Lynch syndrome families and correlate molecular features with prostate cancer risk.

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. The cumulative lifetime risk of prostate cancer (to age 80 y) was 30.0% (95% CI, 16.54%–41.30%; P = .07) in carriers of MMR gene pathogenic variants, whereas it was 17.84% in the general population, according to the Surveillance, Epidemiology, and End Results (SEER) Program estimates. There was a trend of increased prostate cancer risk in carriers of pathogenic variants by age 50 years, where the risk was 0.64% (95% CI, 0.24%–1.01%; P = .06), compared with a risk of 0.26% in the general population. Overall, the HR (to age 80 y) for prostate cancer in carriers of MMR gene pathogenic variants in the combined data set was 1.99 (95% CI, 1.31–3.03; P = .0013). Among men aged 20 to 59 years, the HR was 2.48 (95% CI, 1.34–4.59; P = .0038).

A systematic review and meta-analysis that included 23 studies (6 studies with molecular characterization and 18 risk studies, of which 12 studies quantified risk for prostate cancer) reported an association of prostate cancer with Lynch syndrome. In the six molecular studies included in the analysis, 73% (95% CI, 57%–85%) of prostate cancers in carriers of MMR gene pathogenic variants were MMR deficient. The RR of prostate cancer in carriers of MMR gene pathogenic variants was estimated to be 3.67 (95% CI, 2.32–6.67). Of the twelve risk studies, the RR of prostate cancer ranged from 2.11 to 2.28, compared with that seen in the general population depending on carrier status, prior diagnosis of colorectal cancer, or unknown male carrier status from families with a known pathogenic variant.

A study from three sites participating in the Colon Cancer Family Registry examined 32 cases of prostate cancer (mean age at diagnosis, 62 y; standard deviation, 8 y) in men with a documented MMR gene pathogenic variant (23 MSH2 carriers, 5 MLH1 carriers, and 4 MSH6 carriers). Seventy-two percent (n = 23) had a previous diagnosis of colorectal cancer. Immunohistochemistry was used to assess MMR protein loss, which was observed in 22 tumors (69%); the pattern of loss of protein expression was 100% concordant with the germline pathogenic variant. The RR of prostate cancer was highest in carriers of MSH2 pathogenic variants (RR, 5.8; 95% CI, 2.6–20.9); the RRs in carriers of MLH1 and MSH6 pathogenic variants were 1.7 (95% CI, 1.1–6.7) and 1.3 (95% CI, 1.1–5.3), respectively. Gleason scores ranged from 5 to 10; two tumors had a Gleason score of 5; 22 tumors had a Gleason score of 6 or 7; and eight tumors had a Gleason score higher than 8. Sixty-seven percent (12 of 18) of the tumors were found to have perineural invasion, and 47% (9 of 19) had extracapsular invasion. A large observational cohort study, which included more than 6,000 MMR-variant carriers, reported an increased cumulative incidence of prostate cancer by age 70 years for specific MMR genes, as follows: MLH1 (7.0; 95% CI, 4.2–11.9), MSH2 (15.9; 95% CI, 11.2–22.5), and PMS2 (4.6; 95% CI, 0.8–67.5). No significant increase in prostate cancer incidence was reported for MSH6.

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

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. Pathogenic variants in MSH2 are associated with Lynch syndrome and an increase in prostate cancer risk. For more information on EPCAM and MSH2, see the Gene-specific considerations and associated CRC risk section or the Lynch Syndrome section in Genetics of Colorectal Cancer. Thus far, studies have not found an association between increased prostate cancer risk and EPCAM pathogenic variants.

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. In the presence of DNA damage, the ATM protein is involved in mediating cell cycle arrest, DNA repair, and apoptosis. Given evidence of other cancer risks in heterozygous ATM carriers, evidence of an association with prostate cancer susceptibility continues to emerge. A prospective case series of 10,317 Danish individuals who had a 36-year follow-up period, during which 2,056 individuals developed cancer, found that the ATM Ser49Cys variant was associated with increased prostate cancer risk (HR, 2.3; 95% CI, 1.1–5.0). A retrospective case series of 692 men with metastatic prostate cancer, who were not selected based on a family history of cancer or the patient's age at cancer diagnosis, found that 1.6% of participants (11 of 692) had an ATM pathogenic variant. Multiple independent reports have shown that the ATM P1054R variant, which is found in 2% of Europeans, is associated with increased prostate cancer risk. For example, the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium found an OR of 1.16 (95% CI, 1.10–1.22) for the ATM P1054 variant's association with prostate cancer risk. A subsequent PRACTICAL consortium study had 14 groups (five from North America, six from Europe, and two from Australia) and 8,913 participants (5,560 cases and 3,353 controls). Next-generation ATM sequencing data were standardized and ClinVar classifications were used to categorize the variants as Tier 1 (likely pathogenic) or Tier 2 (potentially deleterious). Prostate cancer risk in Tier 1 variants had an OR of 4.4 (95% CI, 2.0–9.5).

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 ) were found to have a CHEK2 pathogenic variant. A systematic review and meta-analysis from eight retrospective cohort studies examining the relationship between CHEK2 variants (1100delC, IVS2+1G>A, I157T) and prostate cancer confirmed the association of the 1100delC (OR, 3.29; 95% CI, 1.85–5.85; P = .00) and I157T (OR, 1.80; 95% CI, 1.51–2.14; P = .00) variants with prostate cancer susceptibility. A genome-wide association study (GWAS) focusing on African American cases and controls identified a missense variant, I448S, which is associated with prostate cancer (risk allele frequency, 1.5%; OR, 1.62; 95% CI, 1.39–1.89, P = 7.50 × 10-10). Further studies of CHEK2 in large diverse populations are warranted.

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. In a Dutch case series of 180 families meeting either classic Li-Fraumeni syndrome (LFS) or Li-Fraumeni–like (LFL) family history criteria, a deleterious TP53 variant was identified in 24 families with one case of prostate cancer found in each group (LFS or LFL). Prostate cancer risks varied on the basis of the family history criteria with LFS (RR, 0.50; 95% CI, 0.01–3.00) and LFL (RR, 4.90; 95% CI, 0.10–27.00). In a French case series of 415 families with a deleterious TP53 variant, four prostate cancers were reported, with a mean age at diagnosis of 63 years (range, 57–71 y).

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, although additional studies to clarify the association with this gene are warranted.

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. A prospective cohort of men with prostate cancer diagnosed between 1999 and 2015 in Poland confirmed the association of the NBN 657del5 variant and prostate cancer (OR, 2.5; P .001) and mortality (HR, 1.6; P = .001), which remained significant after adjusting for age at diagnosis, PSA, stage, and grade. The risk of prostate cancer in NBN 657del5 carriers is influenced by the genotype at the E185Q polymorphism.

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. Two studies were published using data from a clinical testing laboratory database. The first study evaluated 1,328 men with prostate cancer and reported an overall pathogenic variant rate of 15.6%, including 10.9% in DNA repair genes. A second study involved a larger cohort of 3,607 men with prostate cancer, some of whom had been included in the prior publication. The reported pathogenic variant rate was 17.2%. Overall, pathogenic variant rates by gene were consistently reported between the two studies and were as follows: BRCA2, 4.74%; CHEK2, 2.88%; ATM, 2.03%; and BRCA1, 1.25%. The most commonly aberrant gene in this cohort was BRCA2. The first publication reported associations between family history of breast cancer and high Gleason score (≥8). The second publication focused on the percentage of men with pathogenic variants who met National Comprehensive Cancer Network national guidelines for genetic testing and found that 229 individuals (37%) with pathogenic variants in this cohort did not meet guidelines for genetic testing. A systematic evidence review examined the median prevalence of pathogenic germline variants in the DNA damage-response pathway, including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. The overall prevalence was 18.6% (range, 17.2%–19%; n = 1,712) for general prostate cancer, 11.6% (range, 11.4%–11.8%; n = 1,261) for metastatic prostate cancer, 8.3% (range, 7.5%–9.1%; n = 738) for metastatic castration-resistant prostate cancer, and 29.3% (range, 7.3%–92.67%; n = 327) for familial prostate cancer.

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. The study found strong associations for BRCA2 (OR, 5.65; 95% CI, 3.55–9.32), HOXB13 (OR, 4.73; 95% CI, 2.84–8.19), and ATM (OR, 2.86; 95% CI, 1.63–5.15). The study supports a population-specific assessment of the genetic contribution to prostate cancer risk.

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. Interestingly, 8% of these variants were pathogenic and present in the germline. Another study focused on tumor-normal sequencing of advanced and metastatic cancers identified germline pathogenic variants in 19.6% of men (71 of 362) with prostate cancer. Germline pathogenic variants were found in BRCA1, BRCA2, MSH2, MSH6, PALB2, PMS2, ATM, BRIP1, NBN, as well as other genes. These and other studies are summarized in Table 9. The contribution of germline variants identified from large sequencing efforts to inherited prostate cancer predisposition requires molecular confirmation of genes not classically linked to prostate cancer risk.

Table 9. Summary of Tumor Sequencing Studies With Germline Findings

Common Risk Variants and Polygenic Risk Scores for Prostate Cancer

GWAS and SNPs

• GWAS can identify inherited genetic variants that influence a specific phenotype, such as risk of a particular disease.
• For complex diseases, such as prostate cancer, risk of developing the disease is the product of multiple genetic and environmental factors; each individual factor contributes relatively little to overall risk.
• To date, GWAS have discovered more than 250 common genetic variants associated with prostate cancer risk.
• Individuals can be genotyped for all known prostate cancer risk markers relatively easily; but, to date, studies have not demonstrated that this information substantially refines risk estimates from commonly used variables, such as family history.
• The clinical relevance of variants identified from GWAS remains unclear.

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 that time, more than ten genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions. The population-attributable risk of prostate cancer from the 8q24 risk alleles reported to date is 9.4%.

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. The most convincing associations reported to date for men of European ancestry are annotated in the National Human Genome Research Institute GWAS catalog.

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. Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are annotated in the National Human Genome Research Institute GWAS catalog.

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. The majority of risk alleles (approximately 83%) are shared across African American and European American populations. Three independent associations were subsequently replicated. All three variants were within or near long noncoding RNAs (lncRNAs) previously associated with prostate cancer, and two of the variants were unique 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. Additionally, risk regions that are unique to these ancestral groups were identified (for more information, see the National Human Genome Research Institute GWAS catalog). Ongoing work in larger cohorts will validate and expand upon these findings.

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. Ongoing research attempts to uncover the remaining portion of genetic risk. In the meantime, efforts have been made to utilize the established portions of inherited prostate cancer and create clinically useful metrics for disease risk. Risk variant burden within individuals subjects has been used to generate a PRS. Associations between PRS and disease risk clearly exist. However, it remains unclear whether screening PRSs can appreciably influence long-term outcomes.

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. In 2021, this scoring system, which accounts for genetic dose (i.e., homozygosity vs. heterozygosity) and strength of prostate cancer risk association, was applied to a multi-ethnic cohort of over 100,000 prostate cancer cases and 100,000 controls. This scoring system used 269 known risk variants. In this study, the PRS was called a genetic risk score (GRS). When focusing on men in the top decile of GRSs and comparing them to men in the middle of the distribution, men with European ancestry had an OR of 5.06 (95% CI, 4.84–5.29), and men with African ancestry had an OR of 3.74 (95% CI, 3.36–4.17). When comparing across ethnic groups (with individuals of European, African, East Asian, and Hispanic ancestries) and across all deciles, men with African ancestry were at the highest risk of developing prostate cancer, with a mean GRS that was 2.18-times higher than that of men with European ancestry. Men with East Asian ancestry had a mean GRS that was 0.73-times lower than that of men with European ancestry.

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. However, initial studies suggested that these associations were modest when compared with those in the general population. This is likely because BRCA1 and BRCA2 carriers have a substantially increased risk of developing prostate cancer than individuals in the general population.

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 , 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. Another community-based study (BARCODE1) of 5,000 men aged 55 to 69 years in the United Kingdom involves genotyping for 167 risk SNVs, with men in the top 10% of the PRS undergoing prostate biopsies. This study should provide additional information on the potential clinical utility of the PRS for guiding prostate cancer screening protocols. PRSs have been shown to be additive to risk attributed to rare pathogenic alleles, including BRCA1/BRCA2 and HOXB13.

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. SNP carriers in the high-risk quartile had an increased risk to develop prostate cancer (RR, 1.97; 95% CI, 1.87–2.07). Men in the high-risk quartile also had an increased C-statistic for differentiating prostate cancer incidence when prostate cancer risk–associated SNP burden was added to family history and rare pathogenic variant status (C-statistic for family history, 0.58; C-statistic for pathogenic variant status, 0.67).

Research focused on the associated risk of prostate cancer and the predictability of PRSs is ongoing. In an independent cohort of over 13,000 men, a panel of 261 GWAS-derived risk variants significantly predicted disease risk. Disease risk was best predicted at the highest and lowest deciles, where the highest decile represented the largest risk variant burden, and the lowest decile represented the smallest risk variant burden. In the top decile, the OR for prostate cancer diagnosis was 3.81 (95% CI, 1.48–10.19) in men of African ancestry and 3.89 (95% CI, 3.24– 4.68) in men of European ancestry when compared with men who were at an average risk of developing prostate cancer. In the lowest decile, the ORs were 0.15 (95% CI, 0.01–0.92) and 0.34 (95% CI, 0.25–0.46) in men of African ancestry and men of European ancestry, respectively.

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. As GWAS elucidate these networks, it is hoped that new therapies and chemopreventive strategies will follow.

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.

This section addresses the impact of genetics on prostate cancer screening, surveillance, and 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%. Screening strategies (frequency of PSA measurements or inclusion of DRE) and PSA cutoff for biopsy varied among these studies, which may have influenced this range of PPV. Cancer detection rates among high-risk men have been reported to be in the range of 4.75% to 22%. Most cancers detected were of intermediate Gleason score (5–7), with Gleason scores of 8 or higher being detected in some high-risk men. Overall, there is limited information about the net benefits and harms of screening men at higher risk of prostate cancer. In addition, there is little evidence to support specific screening approaches in prostate cancer families at high risk. Risks and benefits of routine screening in the general population are discussed in Prostate Cancer Screening. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. A summary of prostate cancer screening recommendations for high-risk men by professional organizations is shown in Table 10 and Table 11.

Table 10. Available Recommendations for Prostate Cancer Screening in BRCA1, BRCA2, and HOXB13 Carriers

Table 11. Summary of Prostate Cancer Screening Recommendations for Men Based on Family History, Race, and Ethnicity

Level of evidence: 5

Screening in carriers of BRCA pathogenic 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. The study recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 noncarriers; 731 BRCA2 carriers, 428 BRCA2 noncarriers). A total of 199 men (8%) presented with PSA levels higher than 3.0 ng/mL, which was the study PSA cutoff for recommending a biopsy. The overall cancer detection rate was 36.4% (59 prostate cancers diagnosed among 162 biopsies). Prostate cancer by BRCA pathogenic variant status was as follows: BRCA1 carriers (n = 18), BRCA1 noncarriers (n = 10); BRCA2 carriers (n = 24), BRCA2 noncarriers (n = 7). Using published stage and grade criteria for risk classification, intermediate- or high-risk tumors were diagnosed in 11 of 18 BRCA1 carriers (61%), 8 of 10 BRCA1 noncarriers (80%), 17 of 24 BRCA2 carriers (71%), and 3 of 7 BRCA2 noncarriers (43%). The PPV of PSA with a biopsy threshold of 3.0 ng/mL was 48% in carriers of BRCA2 pathogenic variants, 33.3% in BRCA2 noncarriers, 37.5% in BRCA1 carriers, and 23.3% in BRCA1 noncarriers. Ninety-five percent of the men were White; therefore, the results cannot be generalized to all ethnic groups.

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 polymerase 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. Table 12 summarizes some of the published precision oncology and precision management studies.

Table 12. Summary of Precision Oncology or Precision Management Studies Involving Germline Pathogenic Variant Status