Genes With Potential Clinical Relevance in Prostate Cancer Risk
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 it 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
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 7.
|Study||Population||Prostate Cancer Risk (BRCA1)||Prostate Cancer Risk (BRCA2)|
|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.|
|BCLC (1999) ||BCLC family set that included 173 BRCA2 linkage– or mutation–positive families, among which there were 3,728 individuals and 333 cancersa||Not assessed||Overall: RR, 4.65 (95% CI, 3.48–6.22)|
|Men <65 y: RR, 7.33 (95% CI, 4.66–11.52)|
|Thompson et al. (2001) ||BCLC family set that included 164 BRCA2 mutation–positive families, among which there were 3,728 individuals and 333 cancersa||Not assessed||OCCR: RR, 0.52 (95% CI, 0.24–1.00)|
|Thompson et al. (2002) ||BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were BRCA1 mutation carriers; 1,106 were tested noncarriers, and 8,496 were not tested for mutations||Overall: RR, 1.07 (95% CI, 0.75–1.54)||Not assessed|
|Men younger than 65 y: RR, 1.82 (95% CI, 1.01–3.29)|
Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline 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. In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.
Prevalence of BRCA founder mutations in men with prostate cancer
Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[6-8] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of 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% confidence interval [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 Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks 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). 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 age 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 8 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.
|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) ||979 consecutive AJ men from Israel diagnosed with prostate cancer between 1994 and 1995||Prevalence 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 Israel||Cases: 16 (1.7%)||Cases: 14 (1.5%)||185delAG: OR, 2.52 (95% CI, 1.05–6.04)||OR, 2.02 (95% CI, 0.16–5.72)||There was no evidence of unique or specific histopathology findings within the 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) ||251 unselected AJ men treated for prostate cancer between 2000 and 2002||1,472 AJ men with no history of cancer||Cases: 5 (2.0%)||Cases: 8 (3.2%)||OR, 2.20 (95% CI, 0.72–6.70)||OR, 4.78 (95% CI, 1.87–12.25)|
|Controls: 12 (0.8%)||Controls: 16 (1.1%)|
|Agalliu et al. (2009) ||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 cancer||Cases: 12 (1.2%)||Cases: 18 (1.9%)||OR, 1.39 (95% CI, 0.60–3.22)||OR, 1.92 (95% CI, 0.91–4.07)||Gleason score 7–10 prostate cancer was more common in 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) ||832 AJ men diagnosed with localized prostate cancer between 1988 and 2007||454 AJ men with no history of cancer||Noncarriers: 806 (96.9%)||Noncarriers: 447 (98.5%)||OR, 0.38 (95% CI, 0.05–2.75)||OR, 3.18 (95% CI, 1.52–6.66)||The BRCA1 5382insC founder 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.
The association between prostate cancer and mutations in BRCA1 and BRCA2 has also been studied in other populations. Table 9 summarizes studies that used case-control methods to examine the prevalence of BRCA mutations among men with prostate cancer from other varied populations.
|Study||Population||Controls||Mutation Frequency (BRCA1)||Mutation Frequency (BRCA2)||Prostate Cancer Risk (BRCA1)||Prostate Cancer Risk (BRCA2)||Comments|
|CI = confidence interval; OR = odds ratio; RR = relative risk; SIR = standardized incidence ratio.|
|Johannesdottir et al. (1996) ||75 Icelandic men diagnosed with prostate cancer <65 y, between 1983 and 1992, with available archival tissue blocks||499 randomly selected DNA samples from the Icelandic National Diet Survey||Not assessed||Cases: 999del5 (2.7%)||Not assessed||999del5: RR, 2.5 (95% CI, 0.49–18.4)|
|Eerola et al. (2001) ||107 Finnish hereditary breast cancer families defined as having three first- or second-degree relatives with breast or ovarian cancer at any age||Finnish population based on gender, age, and calendar period–specific incidence rates||Not assessed||Not assessed||SIR, 1.0 (95% CI, 0.0–3.9)||SIR, 4.9 (95% CI, 1.8–11.0)|
|Cybulski et al. (2013) ||3,750 Polish men with prostate cancer unselected for age or family history and diagnosed between 1999 and 2012||3,956 Polish men with no history of cancer aged 23–90 y||Cases: 14 (0.4%)||Not assessed||Any BRCA1 mutation: OR, 0.9; (95% CI, 0.4–1.8)||Not assessed||Prostate cancer risk was greater in familial cases and cases diagnosed <60 y.|
|4153delA: OR, 5.3 (95% CI, 0.6–45.2)|
|Controls: 17 (0.4%)||5382insC: OR, 0.5 (95% CI, 0.2–1.3)|
|C61G: OR, 1.1 (95% CI, 1.6–2.2)|
These data suggest that prostate cancer risk in BRCA1/2 mutation carriers varies with the location of the mutation (i.e., there is a correlation between genotype and phenotype).[17,18,20] These observations might explain some of the inconsistencies encountered in prior studies of these associations, since varied populations may have differences in the proportion of persons with specific pathogenic BRCA1/2 mutations.
Several case series have also explored the role of BRCA1 and BRCA2 mutations and prostate cancer risk.
|Study||Population||Mutation Frequency (BRCA1)||Mutation Frequency (BRCA2)||Prostate Cancer Risk (BRCA1)||Prostate Cancer Risk (BRCA2)||Comments|
|CI = confidence interval; MLPA = multiplex ligation-dependent probe amplification; RR = relative risk.|
|aEstimate calculated using relative risk data in UK general population.|
|Agalliu et al. (2007) ||290 men (white, n = 257; African American, n = 33) diagnosed with prostate cancer <55 y and unselected for family history||Not assessed||2 (0.69%)||Not assessed||RR, 7.8 (95% CI, 1.8–9.4)||No 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) ||266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; median age at prostate cancer diagnosis: 58 y||Not assessed||0 (0%)||Not assessed||Not assessed||31 nonsynonymous variations were identified; no truncating or deleterious mutations were detected.|
|Tryggvadóttir et al. (2007) ||527 men diagnosed with prostate cancer between 1955 and 2004||Not assessed||30/527 (5.7%) carried the Icelandic founder mutation 999del5||Not assessed||Not assessed||The 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) ||1,832 men diagnosed with prostate cancer between ages 36 and 88 y who participated in the UK Genetic Prostate Cancer Study||Not assessed||Overall: 19/1,832 (1.03%)||Not assessed||RR, 8.6a (95% CI, 5.1–12.6)||MLPA was not used; therefore, the 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) ||913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; included 821 cases diagnosed between ages 36 and 65 y, regardless of family history, and 92 cases diagnosed >65 y with a family history of prostate cancer||All cases: 4/886 (0.45%)||Not assessed||RR, 3.75a (95% CI, 1.02–9.6)||Not assessed||Quality-control assessment after sequencing excluded 27 cases, resulting in 886 included in the final analysis.|
|Cases ≤65 y: 3/802 (0.37%)|
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.
Prostate cancer aggressiveness in BRCA mutation carriers
The studies summarized in Table 11 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 mutation.
|Study||Population||Controls||Gleason Scorea||PSAa||Tumor Stage or Gradea||Comments|
|AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OR = odds ratio; PSA = prostate-specific antigen.|
|aMeasures of prostate cancer aggressiveness.|
|Tryggvadóttir et al. (2007) ||30 men diagnosed with prostate cancer who were BRCA2 999del5 founder mutation carriers||59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 mutation||Gleason score 7–10:||Not assessed||Stage IV at diagnosis:|
|– Cases: 84%||– Cases: 55.2%|
|– Controls: 52.7%||– Controls: 24.6%|
|Agalliu et al. (2009) ||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 cancer||Gleason score 7–10:||Not assessed||Not 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) ||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 series||1,587 age- and stage-matched men with prostate cancer||Not assessed||PSA ≥25 ng/mL: HR, 1.39 (95% CI, 1.04–1.86)||Stage T3: HR, 1.19 (95% CI, 0.68–2.05)|
|Stage T4: HR, 1.87 (95% CI, 1.00–3.48)|
|Grade 2: HR, 2.24 (95% CI, 1.03–4.88)|
|Grade 3: HR, 3.94 (95% CI, 1.78–8.73)|
|Gallagher et al. (2010) ||832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were six BRCA1 mutation carriers and 20 BRCA2 mutation carriers||454 AJ men with no history of cancer||Gleason score 7–10:||Not assessed||Not assessed||The 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) ||40 men diagnosed with prostate cancer who were BRCA2 mutation carriers from 30 familial breast cancer families from Australia and New Zealand||97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA mutation found in the family||Gleason score ≥8:||PSA 10–100 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: 44.7% (17/38)|
|– BRCA2 mutations: 65.8% (25/38)||– Controls: 27.9% (27/97)|
|PSA >101 ng/mL:|
|– Controls: 33.0% (25/97)||– BRCA2 mutations: 10% (4/40)||– Controls: 22.6% (21/97)|
|–Controls: 2.1% (2/97)|
|Castro et al. (2013) ||2,019 men diagnosed with prostate cancer from the United Kingdom, of whom 18 were BRCA1 mutation carriers and 61 were BRCA2 mutation carriers||1,940 men who were BRCA1/2 noncarriers||Gleason score >8:||BRCA1 median PSA: 8.9 (range, 0.7–3,000)||Stage ≥pT3 at presentation:||Nodal metastasis and distant metastasis were higher in men with a BRCA mutation than in controls.|
|– BRCA1 mutations: 27.8% (5/18)||– BRCA1: 38.9% (7/18)|
|– BRCA2 mutations: 37.7% (23/61)||BRCA2 median PSA: 15.1 (range, 0.5–761)||– BRCA2 : 49.2% (30/61)|
|– Controls 15.4% (299/1,940)||Controls median PSA: 11.3 (range, 0.2–7,800)||– Controls: 31.7% (616/1,940)|
These studies suggest that prostate cancer in BRCA mutation carriers may be associated with features of aggressive disease, including higher Gleason score, higher prostate-specific antigen (PSA) level at diagnosis, and higher tumor stage and/or grade at diagnosis, a finding that warrants consideration as patients undergo cancer risk assessment and genetic counseling.
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. To further assess this observation, case-control studies were conducted (summarized in Table 12).
|Study||Population||Controls||Prostate Cancer–Specific Survival||Overall Survival||Comments|
|CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen.|
|Tryggvadóttir et al. (2007) ||30 men diagnosed with prostate cancer who were BRCA2 999del5 founder mutation carriers||59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 mutation||BRCA2 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) ||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 series||1,587 age- and stage-matched men with prostate cancer||Not assessed||Overall 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) ||832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 BRCA1 mutation carriers and 20 BRCA2 mutation carriers||454 AJ men with no history of cancer||After adjusting for stage, PSA, Gleason score, and therapy received:||Not assessed||The 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 carriers had a greater risk of death due to prostate cancer (HR, 5.48; 95% CI, 2.03–14.79; P = .001).|
|Thorne et al. (2011) ||40 men diagnosed with prostate cancer who were BRCA2 mutation carriers from 30 familial breast cancer families from Australia and New Zealand||97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA mutation found in the family||BRCA2 carriers were shown to have an increased risk of prostate cancer–specific mortality (HR, 4.5; 95% CI, 2.12–9.52; P = 8.9 × 10-5), compared with noncarrier controls.||BRCA2 carriers were shown to have an increased risk of death (HR, 3.12; 95% CI, 1.64–6.14; P = 3.0 × 10-4), compared with noncarrier controls.||There were too few BRCA1 carriers available to include in the analysis.|
|Castro et al. (2013) ||2,019 men diagnosed with prostate cancer from the United Kingdom, of whom 18 were BRCA1 mutation carriers and 61 were BRCA2 mutation carriers||1,940 men who were BRCA1/2 noncarriers||Prostate cancer–specific survival at 5 years:||Overall survival at 5 years:||For localized prostate cancer, metastasis-free survival was also higher in controls than in mutation carriers (93% vs. 77%; HR, 2.7).|
|– BRCA1: 80.8 (95% CI, 56.9–100)||– BRCA1: 82.5 (95% CI, 60.4–100)|
|– BRCA2: 67.9 (95% CI 53.4–82.4)||– BRCA2: 57.9 (95% CI, 43.4–72.4)|
|– Controls: 90.6 (95% CI 88.8–92.4)||– Controls: 86.4 (95% CI, 84.4–88.4)|
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. 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. 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. 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 single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kilobase region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (odds ratio [OR], 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.
Mismatch Repair (MMR) Genes
Four genes are implicated in MMR, namely MLH1, MSH2, MSH6, and PMS2. Germline mutations in these four genes have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in families, including endometrial, ovarian, and duodenal cancers; and transitional cell cancers of the ureter and renal pelvis. Scattered case reports have suggested that prostate cancer may be observed in men harboring an MMR gene mutation. 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. 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. 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.
One study that included two familial cancer registries found an increased cumulative incidence and risk of prostate cancer among 198 independent mutation-positive families with Lynch syndrome. The cumulative lifetime risk of prostate cancer (to age 80 years) was 30.0% in MMR mutation carriers (95% CI, 16.54–41.30; P = .07), whereas it was 17.84% in the general population, according to the Surveillance, Epidemiology, and End Results Program estimates. There was a trend of increased prostate cancer risk in mutation carriers by age 50 years, where the risk was 0.64% (95% CI, 0.24–1.01; P = .06), compared with a risk of 0.26% in the general population. Overall, the hazard ratio (HR) (to age 80 years) for prostate cancer in MMR mutation carriers 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).
Although the risk of prostate cancer appears to be elevated in families with Lynch syndrome, strategies for germline testing for MMR gene mutations in index prostate cancer patients remain to be determined.
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). 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 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 age at diagnosis: 1.2%.
- Control subjects: 0.1% to 0.2%.
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 mutation was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E mutation was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10-6).
Additional studies have emerged that better define the carrier frequency, prostate cancer risk, and penetrance associated with the HOXB13 G84E mutation. This mutation appears to be restricted to white men, primarily of European descent.[39,41,42] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases. A pooled analysis that included 9,016 cases and 9,678 controls of European Americans found an overall G84E mutation frequency of 1.34% among cases and 0.28% among controls.
Risk of prostate cancer by HOXB13 G84E mutation 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 mutations 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 mutation 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. One population-based, case-control study from the United States confirmed the association of the G84E mutation 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 Ashkenazi Jewish ancestry who carried the G84E mutation.
Penetrance estimates for prostate cancer development in HOXB13 G84E mutation carriers are also being reported. One study from Sweden estimated a 33% lifetime risk of prostate cancer among G84E carriers. Another study from Australia reported age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.
HOXB13 plays a role in prostate cancer development and interacts with the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene identified to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility and implications for genetic counseling regarding the HOXB13 G84E mutation have yet to be defined.
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