Rare germline mutations in African American men diagnosed with early-onset prostate cancer.

BACKGROUND: African Americans have both a higher incidence of prostate cancer and greater disease-specific mortality compared with non-Hispanic whites. Historically, the investigation of the contribution of rare genetic variants to prostate cancer in African American men has been hampered by low participation in large genetic studies, particularly those focused on early-onset and familial disease. METHODS: We sequenced 160 genes purported to be involved in carcinogenic pathways in germline DNA samples collected from 96 African American men diagnosed with early-onset prostate cancer (≤55 years at diagnosis). REVEL software was used to determine the pathogenic potential of observed missense variants. RESULTS: We observed three protein-truncating mutations, one in BRCA2 and two in BRIP1 in three African American men diagnosed with early-onset prostate cancer. Furthermore, we observed five rare, mostly private, missense variants among four genes (BRCA1, BRCA2, PMS2, and ATM) that were predicted to be deleterious and hence likely pathogenic in our patient sample. CONCLUSIONS: Protein-truncating mutations in BRCA2 and BRIP1 were discovered in African American men diagnosed with early-onset prostate cancer. Further study is necessary to determine the role of rare, missense variants to prostate cancer incidence, and progression in this group of high-risk men.

Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

Germline mutations in HOXB13 and prostate-cancer risk.

BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS: We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS: Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.).

Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer.

BACKGROUND: Family history of prostate cancer is a well-recognized risk factor. Previous linkage studies have reported a putative prostate cancer susceptibility locus at chromosome 17q21-22. SPOP (Speckle-type POZ protein) maps to the 17q21-22 candidate linkage region and is one of the most frequently mutated genes in sporadic prostate cancers. METHODS: We performed targeted next generation sequencing to analyze 2009 exons from 202 genes in a candidate linkage region on chromosome 17q21-22 using 94 unrelated familial prostate cancer cases from the University of Michigan Prostate Cancer Genetics Project (n=54) and Johns Hopkins University (n=40) including the exons and UTRs of SPOP. RESULTS: We identified a novel SPOP missense mutation (N296I) in a man with prostate cancer diagnosed at age 43. This mutation completely segregates with prostate cancer affection status among the men in this family. The N296I mutation resides within the evolutionarily conserved Bric-a-brac, Tramtrack, Broad-complex (BTB) domain, involved in recruiting targets to Cul3 for degradation. Analysis of the prostate tumor from this individual verified the presence of heterozygous N296I as well as an ERG fusion. CONCLUSIONS: We have discovered a novel mutation in SPOP that tracks with prostate cancer within a family and is predicted to be deleterious. Taken together, our results implicate SPOP as a candidate gene for hereditary prostate cancer.

Mutational landscape of candidate genes in familial prostate cancer.

BACKGROUND: Family history is a major risk factor for prostate cancer (PCa), suggesting a genetic component to the disease. However, traditional linkage and association studies have failed to fully elucidate the underlying genetic basis of familial PCa. METHODS: Here, we use a candidate gene approach to identify potential PCa susceptibility variants in whole exome sequencing data from familial PCa cases. Six hundred ninety-seven candidate genes were identified based on function, location near a known chromosome 17 linkage signal, and/or previous association with prostate or other cancers. Single nucleotide variants (SNVs) in these candidate genes were identified in whole exome sequence data from 33 PCa cases from 11 multiplex PCa families (3 cases/family). RESULTS: Overall, 4,856 candidate gene SNVs were identified, including 1,052 missense and 10 nonsense variants. Twenty missense variants were shared by all three family members in each family in which they were observed. Additionally, 15 missense variants were shared by two of three family members and predicted to be deleterious by five different algorithms. Four missense variants, BLM Gln123Arg, PARP2 Arg283Gln, LRCC46 Ala295Thr and KIF2B Pro91Leu, and one nonsense variant, CYP3A43 Arg441Ter, showed complete co-segregation with PCa status. Twelve additional variants displayed partial co-segregation with PCa. CONCLUSIONS: Forty-three nonsense and shared, missense variants were identified in our candidate genes. Further research is needed to determine the contribution of these variants to PCa susceptibility.

Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease.

Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy.

OBJECTIVE: To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor, or HOXB13, gene using DNA samples from 9559 men with prostate cancer undergoing radical prostatectomy. PATIENTS AND METHODS: DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and this was confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathological Gleason grade and stage). RESULTS: Of 9559 patients, 128 (1.3%) were heterozygous carriers of G84E. Patients who possessed the variant were more likely to have a family history of prostate cancer than those who did not (46.0 vs 35.4%; P = 0.006). G84E carriers were also more likely to be diagnosed at a younger age than non-carriers (55.2 years vs 58.1 years; P < 0.001). No difference in the proportion of patients diagnosed with high grade or advanced stage tumours according to carrier status was observed. CONCLUSIONS: In the present study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared with homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to selected clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.

HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy.

PURPOSE: The G84E variant of HOXB13 was recently found to be associated with a significantly increased risk of prostate cancer in a case control study. We estimated the prevalence of this mutation in a clinical population of men at risk for prostate cancer who were scheduled to undergo prostate biopsy. MATERIALS AND METHODS: We prospectively collected clinical information and DNA samples from men who underwent diagnostic prostate biopsy between June 2005 and October 2011. We genotyped samples for HOXB13 G84E using the MassARRAY® system. We determined the prevalence of the G84E variant in the overall cohort, among patients with a positive family history and among men age 55 years or younger. RESULTS: A total of 1,175 subjects underwent biopsy, of whom 948 had a DNA sample for analysis. The G84E variant was detected in 4 patients (prevalence 0.42%, 95% CI 0.12-1.08), of whom 3 had prostate cancer on biopsy. None of 301 patients with a positive family history (prevalence 0.00%, 95% CI 0.00-1.22) and 1 of 226 patients age 55 years or younger tested positive (prevalence 0.44%, 95% CI 0.01-2.44). CONCLUSIONS: The HOXB13 G84E variant is rare in this cohort, even among those with a positive family history. Our findings question the utility of testing for this variant among unselected men presenting for a diagnostic prostate biopsy.

Early onset prostate cancer has a significant genetic component.

BACKGROUND: Prostate cancer (PCa) affects more than 190,000 men each year with ∼10% of men diagnosed at ≤55 years, that is, early onset (EO) PCa. Based on historical findings for other cancers, EO PCa likely reflects a stronger underlying genetic etiology. METHODS: We evaluated the association between EO PCa and previously identified single nucleotide polymorphisms (SNPs) in 754 Caucasian cases from the Michigan Prostate Cancer Genetics Project (mean 49.8 years at diagnosis), 2,713 Caucasian controls from Illumina's iControlDB database and 1,163 PCa cases diagnosed at >55 years from the Cancer Genetic Markers of Susceptibility Study (CGEMS). RESULTS: Significant associations existed for 13 of 14 SNPs (rs9364554 on 6q25, rs10486567 on 7p15, rs6465657 on 7q21, rs6983267 on 8q24, rs1447295 on 8q24, rs1571801 on 9q33, rs10993994 on 10q11, rs4962416 on 10q26, rs7931342 on 11q13, rs4430796 on 17q12, rs1859962 on 17q24.3, rs2735839 on 19q13, and rs5945619 on Xp11.22, but not rs2660753 on 3p12). EO PCa cases had a significantly greater cumulative number of risk alleles (mean 12.4) than iControlDB controls (mean 11.2; P = 2.1 × 10(-33)) or CGEMS cases (mean 11.9; P = 1.7 × 10(-5)). Notably, EO PCa cases had a higher frequency of the risk allele than CGEMS cases at 11 of 13 associated SNPs, with significant differences for five SNPs. EO PCa cases diagnosed at <50 (mean 12.8) also had significantly more risk alleles than those diagnosed at 50-55 years (mean 12.1; P = 0.0003). CONCLUSIONS: These results demonstrate the potential for identifying PCa-associated genetic variants by focusing on the subgroup of men diagnosed with EO disease.

Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG).

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.

Genetic variation in glutathione S-transferase omega-1, arsenic methyltransferase and methylene-tetrahydrofolate reductase, arsenic exposure and bladder cancer: a case-control study.

BACKGROUND: Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer. METHODS: Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case-control study in Southeastern Michigan and exposed to low to moderate (<50 µg/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources. RESULTS: While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 µg/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88). CONCLUSIONS: Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings.

Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in African American men: the Flint Men's Health Study.

BACKGROUND: Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States and the second leading cause of cancer-related mortality. African American men have substantially increased risk of both being diagnosed and dying from the disease. Recent genome-wide genetic association studies have identified a number of common single nucleotide genetic polymorphisms (SNPs) that are associated with prostate cancer in men of European descent. Only a small number of studies have evaluated the association between these genetic variants and prostate cancer in African Americans. METHODS: We used logistic regression models to assess the association between prostate cancer in African American men and 24 SNPs from regions previously reported to be associated with prostate cancer in men of European descent. RESULTS: We found nominal evidence (P < 0.05) for association between prostate cancer and three chromosome 8q24 (rs6983561, rs16901979, and rs7000448) and two 10q11 (rs7904463 and rs10740051) SNPs. CONCLUSIONS: We confirm recent reports that 8q24 variants identified to be associated with prostate cancer in men of European descent are also associated with prostate cancer in African Americans. Our report is the first to find evidence of association between SNPs near MSMB and prostate cancer in African Americans. Of note, rs7000448 is in strong linkage disequilibrium with rs10761581 in NCOA4, a SNP that has been implicated to be independently associated, with respect to the widely reported SNP rs10993994 in the nearby gene MSMB, with prostate cancer in men of European descent.

Sequence variation in the mitochondrial gene cytochrome c oxidase subunit I and prostate cancer in African American men.

BACKGROUND: Previous studies have found associations between mitochondrial DNA (mtDNA) mutations and several cancer types. Recently, we found that mutations in the mtDNA gene cytochrome c oxidase subunit 1 (COI) were both linked to and associated with prostate cancer (PCa) in Caucasian men. Here we examine the association between COI mutations and PCa in African American men. METHODS: The entire COI gene was directly sequenced in 132 PCa cases and 135 controls from the Flint Men's Health Study, a community-based sample of African American men with and without PCa. Associations between all variants and PCa were evaluated. RESULTS: We identified 102 COI single nucleotide polymorphisms (SNPs), including 15 missense variants. Overall, the presence of one or more COI missense variants was not significantly associated with PCa. Individually, two SNPs (T6221C and T7389C) were significantly associated with prostate cancer (P < 0.05) and in strong linkage disequilibrium with each other (r(2) > 0.6). CONCLUSIONS: Of the two significantly associated SNPs, one is a synonymous substitution and the other is part of the African-specific mitochondrial haplogroup (L). Additional research will be needed to determine the clinical relevance of these associations in African populations.

Genome-wide linkage scan for prostate cancer susceptibility from the University of Michigan Prostate Cancer Genetics Project: suggestive evidence for linkage at 16q23.

BACKGROUND: Prostate cancer linkage studies have been used to localize rare and presumably highly penetrant cancer susceptibility genes. Underlying genetic heterogeneity, as well as the high sporadic background of the disease, has resulted in many signals that are often not reproducible between research studies. METHODS: We conducted a SNP-based genome wide linkage scan on 131 Caucasian prostate cancer families participating in the University of Michigan Prostate Cancer Genetics Project (PCGP). RESULTS: The strongest evidence for linkage was detected at 16q23 (LOD = 2.70 at rs1079635). Prostate cancer linkage to the same region of 16q23 has been observed by others and the region contains several strong candidate genes including the known prostate cancer tumor suppressor genes ATBF1 and WWOX. This linkage signal was not detected in our prior linkage study on 175 PCGP families, illustrating the genetic heterogeneity underlying prostate cancer susceptibility. CONCLUSIONS: Further linkage studies in combination with tumor analyses from linked families are in progress to identify the putative hereditary prostate cancer gene at 16q23.

Chromosome 8q24 markers: risk of early-onset and familial prostate cancer.

Recent admixture mapping and linkage/association studies have implicated an approximately 1 Mb region on chromosome 8q24 in prostate cancer susceptibility. In a subsequent follow-up investigation, Haiman et al. (Nat Genet 2007;39:638-44) observed significant, independent associations between 7 markers within this region and sporadic prostate cancer risk in a multi-ethnic sample. To clarify the risk associated with hereditary prostate cancer, we tested for prostate cancer association with 6 of these 7 markers in a sample of 1,015 non-Hispanic white men with and without prostate cancer from 403 familial and early-onset prostate cancer families. Single nucleotide polymorphisms (SNPs) rs6983561 and rs6983267 showed the strongest evidence of prostate cancer association. Using a family-based association test, the minor ("C") allele of rs6983561 and the major ("G") allele of rs6983267 were preferentially transmitted to affected men (p < 0.05), with estimated odds ratios (ORs) of 2.26 (95% confidence interval of 1.06-4.83) and 1.30 (95% confidence interval of 0.99-1.71), respectively, for an additive model. Notably, rs6983561 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p = 0.03 versus p = 0.21). Similarly, the association with rs6983267 was (not) statistically significant among men with(out) clinically aggressive disease (p = 0.007 versus p = 0.34). Our results confirm the association of prostate cancer with several of the SNPs on chromosome 8q24 initially reported by Haiman et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset or clinically aggressive disease.

Association between germline variation in the FHIT gene and prostate cancer in Caucasians and African Americans.

Many studies have established that loss of heterozygosity and/or altered expression of the fragile histidine triad (FHIT) gene is a common event in a number of tumor types including prostate carcinoma. Encompassing the most active fragile site in the human genome, FRA3B, FHIT has become the model fragile site-associated tumor suppressor gene. In a recent study, linkage and association between germline genetic variation in FHIT (specifically single nucleotide polymorphism rs760317) and prostate cancer were reported. We sought to confirm this finding in two independent samples: (a) a family-based sample of 817 men with (n = 434) and without (n = 383) prostate cancer from 323 Caucasian families, and (b) a community-based case-control sample of African American men with (n = 133) and without (n = 342) prostate cancer. Using a family-based association test, rs760317 was associated with prostate cancer in Caucasians (P = 0.031), with a reduction in the risk of prostate cancer among carriers of the minor allele (odds ratio, 0.66; 95% confidence interval, 0.42-1.04; P = 0.074). African American carriers experienced a similar risk reduction (odds ratio, 0.63; 95% confidence interval, 0.42-0.96; P = 0.032). These results are remarkably consistent across ethnic samples but are in opposition to results from the original study, which showed an association between the minor allele of rs760317 and an increased risk of prostate cancer. Taken together, the consistently significant but flipped association between single nucleotide polymorphism rs760317 and prostate cancer in three independent samples suggests that rs760317 may be in linkage disequilibrium with one or more prostate cancer susceptibility variants in or near FHIT.

Common variation in the BRCA1 gene and prostate cancer risk.

Rare inactivating mutations in the BRCA1 gene seem to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations (e.g., missense mutations) in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kb region surrounding (and including) the BRCA1 gene. We also used the Genotype-Identity-by-Descent Sharing Test to determine whether our most strongly associated SNP could account for prostate cancer linkage to chromosome 17q21 in a sample of 154 families from our previous genome-wide linkage study. The strongest evidence for prostate cancer association was for a glutamine-to-arginine substitution at codon 356 (Gln(356)Arg) in exon 11 of the BRCA1 gene. The minor (Arg) allele was preferentially transmitted to affected men (P = 0.005 for a dominant model), with an estimated odds ratio of 2.25 (95% confidence interval, 1.21-4.20). Notably, BRCA1 Gln(356)Arg is not in strong linkage disequilibrium with other BRCA1 coding SNPs or any known HapMap SNP on chromosome 17. In addition, Genotype-Identity-by-Descent Sharing Test results suggest that Gln(356)Arg accounts (in part) for our prior evidence of prostate cancer linkage to chromosome 17q21 (P = 0.022). Thus, we have identified a common, nonsynonymous substitution in the BRCA1 gene that is associated with and linked to prostate cancer.

Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.

BACKGROUND: We assessed the evidence for association between 23 recently reported prostate cancer variants and early-onset prostate cancer and the aggregate value of 63 prostate cancer variants for predicting early-onset disease using 931 unrelated men diagnosed with prostate cancer prior to age 56 years and 1,126 male controls. METHODS: Logistic regression models were used to test the evidence for association between the 23 new variants and early-onset prostate cancer. Weighted and unweighted sums of total risk alleles across these 23 variants and 40 established variants were constructed. Weights were based on previously reported effect size estimates. Receiver operating characteristic curves and forest plots, using defined cut-points, were constructed to assess the predictive value of the burden of risk alleles on early-onset disease. RESULTS: Ten of the 23 new variants demonstrated evidence (P < 0.05) for association with early-onset prostate cancer, including four that were significant after multiple test correction. The aggregate burden of risk alleles across the 63 variants was predictive of early-onset prostate cancer (AUC = 0.71 using weighted sums), especially in men with a high burden of total risk alleles. CONCLUSIONS: A high burden of risk alleles is strongly associated with early-onset prostate cancer. IMPACT: Our results provide the first formal replication for several of these 23 new variants and demonstrate that a high burden of common-variant risk alleles is a major risk factor for early-onset prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(5); 766-72. ©2015 AACR.

Identifying susceptibility genes for prostate cancer--a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta.

Polymorphisms in genes that code for enzymes or hormones involved in the synthesis and metabolism of androgens are compelling biological candidates for prostate cancer. Four such genes, CYP17, CYP19, CYP11A1, and LH-beta, are involved in the synthesis and conversion of testosterone to dihydrotestosterone and estradiol. In a study of 715 men with and without prostate cancer from 266 familial and early-onset prostate cancer families, we examined the association between prostate cancer susceptibility and common single-nucleotide polymorphisms in each of these four candidate genes. Family-based association tests revealed a significant association between prostate cancer and a common single-nucleotide polymorphism in CYP17 (P=0.004), with preferential transmission of the minor allele to unaffected men. Conditional logistic regression analysis of 461 discordant sibling pairs from these same families reaffirmed the association between the presence of the minor allele in CYP17 and prostate cancer risk (odds ratio, 0.51; 95% confidence interval, 0.28-0.92). These findings suggest that variation in or around CYP17 predicts susceptibility to prostate cancer. Family-based association tests may be especially valuable in studies of genetic variation and prostate cancer risk because this approach minimizes confounding due to population substructure, which is of particular concern for prostate cancer given the tremendous variation in the worldwide incidence of this disease.