International Consortium of Prostate Cancer Genetics We have been a key part of a consortium of prostate cancer (PC) genetic labs working to identify susceptibility loci for several years. This year the consortium did several things. First, we contributed to an analysis of a previously reported linkage on X27-27 (Bailey Wilson et al., 2012, BMC Med Genet. 13(1):46) showing that genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome. In a second effort, we worked together to validate PC loci published from other genome wide association studies (GWAS) (Jin et al., 2012, Hum Genet. 131: 1095-1102. 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 of Prostate Cancer Genetics (ICPCG). We validated loci on 8q24, 10q11, 11q13, 17q12, 17q24 and Xp11. Finally, we studied the role of chromosomes 4 and 8 which were implicated in a genome wide SNP linkage scan of 762 ICPC families (Lu et al., Prostate 2012, 72:410-26). This validated the locus at 8q24 in the vicinity of the MYC gene as playing a role in susceptibility. Identification and Validation of New Susceptibility Loci Through a Genome-Wide Association Studies We have also collaborated with the PRACTICAL International consortium. Our role, together with collaborators, has been to validate and extend the initial findings. The initial studies were published in 2008 in Nature Genetics (Eeles et al., Nat Genet, 2008, 40:316-21). In a subsequent study we validated these results showing that loci on chromosomes 3, 6, 7, 10, 11 19 and X contained SNPs strongly associated with PC (Kote-Jarai et al., Cancer Epidemiol Biomarkers Prev. 2008, 17: 2052-2061). In the past year the group has expanded the data set (Kote-Jarai et al., Nat Genet. 2011: 43:785-91) and now report on the results of stage three. We identified seven new PC susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 10-8 to P = 2.7 10-24). Markers of Prostate-Specific Mortality, Aggressive Disease, and Recurrence We tested whether variation in selected candidate genes in biological pathways of interest for PC progression could help distinguish patients at higher risk for fatal prostate cancer (Lin et al., Cancr Epidemiol Biomarkres Prev, 2011, 20:1928-36). In this hypothesis-driven study, the Ostrander lab genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 PC cases. We identified 22 top-ranking SNPs (P ≤0.01, FDR ≤0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent cohort. Five SNPs were validated (P ≤0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2-1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried P(trend) = 0.001. This is the first population-based study to show that germline genetic variants provide prognostic information for PC-specific survival. We also therefore undertook a search for genetic variants associated with risk of more aggressive disease (FitzGerald, et al., Cancer Epidemiol Biomarkers Prev 20: 1196-203). A genome-wide scan was conducted in 202 PV cases with an aggressive phenotype and 100 negative controls. A variant on 15q13 was confirmed as most strongly associated with aggressive disease (P(discovery) = 5.20 10(-5), P(validation) = 0.004). Another SNP on 3q26, rs3774315, was found to be associated with PC risk. This study provides suggestive evidence for a genetic predisposition to more aggressive PC and highlights the fact that larger studies are warranted to confirm this supposition and identify further risk variants. Replication of other Studies in PC Replication Finally, we sought to determine if any of the SNPs found in previously published GWAS were specifically associated with PC recurrence (Ahn et al., Clin. Cancer Res, 2011, 17: 1075-81). Twelve SNPs were selected for study in relation to metastatic PC and recurrence, based on their genome-wide association with PC in the Cancer Genetic Markers of Susceptibility (CGEMS). We compared genotypes for the 12 SNPs in cases and controls. MSMB rs10993994 (per variant allele summary RR = 1.24, 95% CI = 1.05-1.48), 8q24 rs4242382 (RR = 1.40, 95% CI = 1.13-1.75), and 8q24 rs6983267 (RR = 0.67, 95% CI = 0.50-0.89) were associated with risk for metastatic prostate cancer. None of the 12 SNPs was associated with PC recurrence. Individual Pathways and Prostate Cancer Risk Multiple biological pathways are implicated in conferring susceptibility to PC. We therefore evaluated PC risk in association with three such pathways. We did a detailed study of genes in the inflammation (Kwon et al., Cancer Epidemiol, 2011, 20: 923-33). A total of 143 tagging and amino acid altering SNPs were genotyped in Caucasian and African American men participating the above mentioned population-based, case-control studies. Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P <0.05) with risk of PC in Caucasians. The most significant effect on risk was seen in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01-0.63). These results suggest that variants in genes within the inflammation pathway may play a role in the development of PC, and highlight the potential importance of the inflammation pathway in PC development and progression. Next, we analyzed the estrogen pathway and evaluated 73 SNPs (Holt et al., 2012;Prostate doi: 10.1002/pros.22534). Risk of PC was found in three genes (ESR1, CYP1A1 and CYP1B1) with CYP1B1 remaining significant after adjusting for multiple comparisons. An association with risk of more aggressive PC was observed in three genes (ERS1, ERS2 and CYP19A1). Our results imply that germline genetic variants in the estrogen pathway might contribute to risk of PC as well. Finally, we examined androgen signaling, which plays a critical role in PC development. A total of 187 SNPs were genotyped. Nine genes (NKX3.1, HSD17B3, AKR1C3, SULT2A1, CYP17A1, KLK3, JAK2, NCOA4 and STAT3) show evidence (p <0.05) for associations with PC risk with the JAK2 SNP remaining significant after correcting for multiple testing (Kwon et al., Cancer Epidemiol Biomarkers Prev. 36:347-353). Five genes (CYP17A1, HSD17B4, JAK2, NCOA4 and SULT2A1) were associated with disease aggressiveness. Our data replicated previously reported association as well as identified novel associations for SNPs in JAK2, HSD17B4 and SULT2A1. Prostate Cancer and African American Men We were also interested in identifying common risk alleles for PC that might contribute to the high rates of PC in men with African ancestry and contributed to 2 relevant studies. In the first, 7788 PC cases and controls of African ancestry were analyzed for 47 previously reported loci (Chang et al., 2011). We identified significant associations at five different loci (JAZF1, MSMB, 11q13, NUT10/11 and 8q24). Therefore, this study validated in men of African descent the association of some, but not all, PC loci originally identified in populations of European decent. The second study evaluated over one million SNPs in 3425 African-American PC cases and 3290 controls (Haiman et al., 2011). A new risk variant on 17q21 was significantly associated with risk of PC (odds ration per allele = 1.51, p = 3.4x10-13). The results highlight the heterogeneity of PC in African American men.

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