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Genetics of Prostate Cancer (PDQ®)

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NCI Highlights

Genes With Potential Clinical Relevance in Prostate Cancer Risk

BRCA1 and BRCA2
        BRCA mutation–associated prostate cancer risk
        Prevalence of BRCA founder mutations in men with prostate cancer
        Prostate cancer aggressiveness in BRCA mutation carriers
        BRCA1/BRCA2 and survival outcomes
        Additional studies involving the BRCA region
Mismatch Repair Genes
HOXB13

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

BRCA1 and BRCA2

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2]

BRCA mutation–associated prostate cancer risk

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

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 2.

Table 2. Case Series of BRCA Mutations in Prostate Cancer
Study Population Prostate Cancer Risk (BRCA1) Prostate Cancer Risk (BRCA2) 
BCLC, 1999 [3]BCLC family set that included 173 BRCA2 linkage or mutation-positive families, among which there were 3,728 individuals and 333 cancersaNot assessedOverall: RR, 4.65 (95% CI, 3.48–6.22)
Men <65 y: RR, 7.33 (95% CI, 4.66–11.52)
Thompson et al., 2001 [4]BCLC family set that included 164 BRCA2 mutation-positive families, among which there were 3,728 individuals and 333 cancersaNot assessedOCCR: RR, 0.52 (95% CI, 0.24–1.00)
Thompson et al., 2002 [1]BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were BRCA1 mutation carriers, 1,106 were tested noncarriers, and 8,496 were not tested for mutationsOverall: RR, 1.07 (95% CI, 0.75–1.54)Not assessed
Men <65 y: RR, 1.82 (95% CI, 1.01–3.29)

BCLC = Breast Cancer Linkage Consortium; CI = confidence interval; OCCR = Ovarian Cancer Cluster Region; RR = relative risk.
aIncludes all cancers except breast, ovarian, and nonmelanoma skin cancers.

A review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[5]

Prevalence of BRCA founder mutations in men with prostate cancer

Ashkenazi Jewish

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi men with prostate cancer.[6-8] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of Ashkenazi Jewish (AJ) ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.7–1.1) for the 185delAG mutation, 0.3% (95% CI, 0.2–0.4) for the 5382insC mutation, and 1.3% (95% CI, 1.0–1.5) for the BRCA2 6174delT mutation.[9-12] (Refer to the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about BRCA1 and BRCA2 genes.) In these studies, the RRs were commonly greater than 1, but only a few have been 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 mutations.

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 mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4–30) among carriers and 3.8% among noncarriers (95% CI, 3.3–4.4).[12] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by the age of 70 years; 95% CI, 6–28). The risk of prostate cancer in male mutation 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 mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations 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 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

The studies summarized in Table 3 used similar case-control methods to examine the prevalence of Ashkenazi founder mutations among Jewish men with prostate cancer and found an overall positive association between founder mutation status and prostate cancer risk.

Table 3. Case-Control Studies in Ashkenazi Jewish Populations of BRCA1 and BRCA2 and Prostate Cancer Risk
Study Population Controls Mutation Frequency (BRCA1) Mutation Frequency (BRCA2) Prostate Cancer Risk (BRCA1) Prostate Cancer Risk (BRCA2) Comments 
AJ = Ashkenazi Jewish; CI = confidence interval; MECC = Molecular Epidemiology of Colorectal Cancer; OR = odds ratio; WAS = Washington Ashkenazi Study.
Guisti et al., 2003 [13]979 consecutive AJ men from Israel diagnosed with prostate cancer between 1994 and 1995Prevalence of founder mutations compared with age-matched controls >50 years with no history of prostate cancer from the WAS study and the MECC study from IsraelCases: 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 mutation-associated prostate cancers.
Controls: 11 (0.81%)Controls: 10 (0.74%)5282insC: OR, 0.22 (95% CI, 0.16–5.72)
Kirchoff et al., 2004 [14]251 unselected AJ men treated for prostate cancer between 2000 and 20021,472 AJ men with no history of cancerCases: 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: 12 (0.8%)Controls: 16 (1.1%)
Agalliu et al., 2009 [15]979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis: 1996)1,251 AJ men with no history of cancerCases: 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 BRCA1 mutation carriers (OR, 2.23; 95% CI, 0.84–5.86) and BRCA2 mutation carriers (OR, 3.18; 95% CI, 1.62–6.24) than in controls.
Controls: 11 (0.9%)Controls: 12 (1.0%)
Gallagher et al., 2010 [16]832 AJ men diagnosed with localized prostate cancer between 1988 and 2007454 AJ men with no history of cancerNoncarriers: 806 (96.9%)Noncarriers: 447 (98.5%)OR, 0.38 (95% CI, 0.05–2.75)OR, 3.18 (95% CI, 1.52–6.66)The BRCA1 5382insC founder mutation was not tested in this series, so it is likely that some carriers of this mutation were not identified. Consequently, BRCA1-related risk may be underestimated. Gleason score 7–10 prostate cancer was more common in BRCA2 mutation carriers (85%) than in noncarriers (57%); P = .0002. BRCA1/2 mutation carriers had significantly greater risk of recurrence and prostate cancer–specific death than did noncarriers.
Cases: 6 (0.7%)Cases: 20 (2.4%)
Controls: 4 (0.9%)Controls: 3 (0.7%)

These studies support the hypothesis that prostate cancer occurs excessively among carriers of AJ founder mutations and suggest that the risk may be greater among men with the BRCA2 founder mutation (6174delT) than among those with one of the BRCA1 founder mutations (185delAG; 5382insC). The magnitude of the BRCA2-associated risks differ 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.[16]

Other populations

The association between prostate cancer and mutations in BRCA1 and BRCA2 has also been studied in other populations.

Three Polish BRCA1 founder mutations (C16G, 4153delA, and 5382insC) were studied in 1,793 Polish prostate cancer cases and 4,570 controls. Overall, the prevalence of the three mutations combined was identical in cases and controls. However, the most common mutation, 5382insC, occurred in 0.06% of cases versus 0.37% of controls, suggesting that this specific variant is not likely to be associated with increased prostate cancer risk. Furthermore, the presence of either of the other two mutations (C16G and 4153delA) was associated with a 3.6-fold increase in prostate cancer risk (P = .045) and an even greater risk (OR, 12; P = .0004) of familial prostate cancer. These data suggest that prostate cancer risk in BRCA1 mutation carriers varies with the location of the mutation (i.e., there is a correlation between genotype and phenotype).[17] This observation might explain some of the inconsistencies encountered in prior studies of this association, since populations may have varied relative to the proportion of persons with specific pathogenic BRCA1 mutations.

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

Table 4. Case Series of BRCA1 and BRCA2 and Prostate Cancer Risk
Study Population Mutation Frequency (BRCA1) Mutation Frequency (BRCA2) Prostate Cancer Risk (BRCA1) Prostate Cancer Risk (BRCA2) Comments 
Agalliu et al., 2007 [18]290 men (Caucasian, n = 257; African American, n = 33) diagnosed with prostate cancer <55 y and unselected for family historyNot assessed2 (0.69%)Not assessedRR, 7.8 (95% CI, 1.8–9.4)No mutations were found in African American men.
The two men with a mutation reported no family history of breast cancer or ovarian cancer.
Agalliu et al., 2007 [19]266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; median age at prostate cancer diagnosis: 58 yNot assessed0 (0%)Not assessedNot assessed31 nonsynonymous variations were identified; no truncating or deleterious mutations were detected.
Tryggvadóttir et al., 2007 [20]527 men diagnosed with prostate cancer between 1955 and 2004Not assessed30/527 (5.7%) carried the Icelandic founder mutation 999del5Not assessedNot assessedThe BRCA2 999del5 mutation was associated with a lower mean age at prostate cancer diagnosis (69 vs. 74 y; P = .002)
Kote-Jarai et al., 2011 [21]1,832 men diagnosed with prostate cancer between ages 36 and 88 y who participated in the UK Genetic Prostate Cancer StudyNot assessedOverall: 19/1,832 (1.03%)Not assessedRR 8.6a (95% CI, 5.1–12.6)MLPA was not used; therefore, the mutation 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 [22]913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; included 821 cases diagnosed between ages 36 and 65 y, regardless of family history, and 92 cases diagnosed >65 y with a family history of prostate cancerAll cases: 4/886 (0.45%)Not assessedRR, 3.75a (95% CI, 1.02–9.6)Not assessedQuality-control assessment after sequencing excluded 27 cases, resulting in 886 included in the final analysis.
Cases ≤65 y: 3/802 (0.37%)

CI = confidence interval; MLPA = multiplex ligation-dependent probe amplification; RR = relative risk.
aEstimate calculated using relative risk data in UK general population.

These case series confirm that mutations in BRCA1 and BRCA2 do not play a significant role in hereditary prostate cancer. However, germline mutations 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.[18]

Prostate cancer aggressiveness in BRCA mutation carriers

The studies summarized in Table 5 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 mutation.

Table 5. Case-Control Studies of BRCA1 and BRCA2 and Prostate Cancer Aggressiveness
Study Population Controls Gleason Scorea PSAa Tumor Stage or Gradea Comments 
Tryggvadóttir et al., 2007 [20]30 men diagnosed with prostate cancer who were BRCA2 999del5 founder mutation carriers59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 mutationGleason score 7–10:Not assessedStage IV at diagnosis:
Cases: 84%Cases: 55.2%
Controls: 52.7%Controls: 24.6%
Agalliu et al., 2009 [15]979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis: 1996)1,251 AJ men with no history of cancerGleason score 7–10:Not assessedNot assessed
BRCA1 185delAG mutation: OR, 3.54 (95% CI, 1.22–10.31)
BRCA2 6174delT mutation: OR, 3.18 (95% CI, 1.37–7.34)
Edwards et al., 2010 [23]21 men diagnosed with prostate cancer who harbored a BRCA2 mutation: 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series1,587 age- and stage-matched men with prostate cancerNot assessedPSA ≥25 ng/mL: HR, 1.39 (95% CI, 1.04–1.86)Stage T3: HR, 1.19 (95% CI, 0.68–2.05)
Stage T4: HR, 1.87 (95% CI, 1.00–3.48)
Grade 2: HR, 2.24 (95% CI, 1.03–4.88)
Grade 3: HR, 3.94 (95% CI, 1.78–8.73)
Gallagher et al., 2010 [16]832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were six BRCA1 mutation carriers and 20 BRCA2 mutation carriers454 AJ men with no history of cancerGleason score 7–10:Not assessedNot assessedThe BRCA1 5382insC founder mutation was not tested in this series.
BRCA2 6174delT mutation: HR, 2.63 (95% CI, 1.23–5.6; P = .001)
Thorne et al., 2011 [24]40 men diagnosed with prostate cancer who were BRCA2 mutation carriers from 30 familial breast cancer families from Australia and New Zealand97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA mutation found in the familyGleason score ≥8:PSA10–100 ng/mL:Stage ≥pT3 at presentation:BRCA2 mutation carriers were more likely to have high-risk disease by D’Amico criteria than were noncarriers (77.5% vs. 58.7%, P = .05).
BRCA2 mutations: 35% (14/40)
BRCA2 mutations: 65.8% (25/38)Controls: 27.9% (27/97)BRCA2 mutations: 44.7% (17/38)
PSA >101 ng/mL:Controls: 22.6% (21/97)
Controls: 33.0% (25/97)BRCA2 mutations: 10% (4/40)
Controls: 2.1% (2/97)

AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OR = odds ratio; PSA = prostate-specific antigen.
aMeasures of prostate cancer aggressiveness.

These studies suggest that prostate cancer in BRCA mutation carriers may be associated with features of aggressive disease, including higher Gleason score, higher PSA level at diagnosis, and higher tumor stage and/or grade at diagnosis, a finding that warrants consideration as patients undergo cancer risk assessment and genetic counseling.

BRCA1/BRCA2 and survival outcomes

Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 mutations 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 mutation and 8 years in 119 men with a BRCA1 mutation. The study suggests that BRCA2 mutation carriers have a poorer survival than BRCA1 mutation carriers.[25] To further assess this observation, case-control studies, which are summarized in Table 6, have been conducted.

Table 6. Case-Control Studies of BRCA1 and BRCA2 and Survival Outcomes
Study Population Controls Prostate Cancer–Specific Survival Overall Survival Comments 
CI = confidence interval; HR = hazard ratio.
Tryggvadóttir et al., 2007 [20]30 men diagnosed with prostate cancer who were BRCA2 999del5 founder mutation carriers59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 mutationBRCA2 999del5 mutation 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 [23]21 men diagnosed with prostate cancer who harbored a BRCA2 mutation: 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series1,587 age- and stage-matched men with prostate cancerNot assessedOverall survival was lower in BRCA2 mutation carriers (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 [16]832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 BRCA1 mutation carriers and 20 BRCA2 mutation carriers454 AJ men with no history of cancerAfter adjusting for stage, PSA, Gleason score, and therapy received:Not assessedThe BRCA1 5382insC founder mutation was not tested in this series.
BRCA1 185delAG mutation carriers had a greater risk of death due to prostate cancer (HR, 5.16; 95% CI, 1.09–24.53; P = .001).
BRCA2 6174delT mutation 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 [24]40 men diagnosed with prostate cancer who were BRCA2 mutation carriers from 30 familial breast cancer families from Australia and New Zealand97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA mutation found in the familyBRCA2 carriers were shown to have an increased risk of prostate cancer–specific mortality (HR, 4.5; 95% CI, 2.12–9.52; P = 8.9 × 10-5), compared with noncarrier controls.BRCA2 carriers were shown to have an increased risk of death (HR, 3.12; 95% CI, 1.64–6.14; P = 3.0 × 10-4), compared with noncarrier controls.There were too few BRCA1 carriers available to include in the analysis.

These findings suggest overall survival and prostate cancer–specific survival may be lower in mutation carriers than in controls.

Additional studies involving the BRCA region

A genome-wide scan for hereditary prostate cancer using 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence of linkage to chromosome 17q markers.[26] 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 mutations using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[27] 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 mutation (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 mutations in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.

In another study from the UM-PCGP, common genetic variation in BRCA1 was examined.[28] 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 prostate cancer, to investigate the association of SNPs tagging common haplotype variation in a 200-kilobase (kb) region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (OR, 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[26]

Mismatch Repair Genes

There are four genes implicated in mismatch repair (MMR), namely MLH1, MSH2, MSH6, and PMS2. Germline mutations in four of the genes implicated in MMR have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in the families, including endometrial, ovarian, and duodenal cancers and transitional cell cancers of the ureter and renal pelvis. Scattered case reports have suggested that prostate cancer may be observed in men harboring an MMR gene mutation.[29] The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male MMR mutation carriers or obligate carriers.[30] 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 years vs. 66.6 years, 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 MMR gene mutation carriers and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNPs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer.[31] 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 MMR mutation–positive families were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer.[32]

HOXB13

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[26] 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.[33] 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).[34] Probands from four families were discovered to have a recurrent mutation (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the mutation. The mutation status was determined in 5,083 additional case subjects and 2,662 control subjects. Carrier frequencies and odds ratios 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 with an age at diagnosis younger than 55 years: 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 age at diagnosis younger than 55 years: 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 age at diagnosis older than 55 years: 1.2%.
  • Control subjects: 0.1% to 0.2%.[34]

Additional rare variants in HOXB13 were also observed. Penetrance estimates of the G84E variant in HOXB13 are under study. HOXB13 plays a role in prostate development and binds to the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene proven to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer, but the clinical utility of testing for this mutation has not yet been defined.

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