Finding Genes for Human Prostate Cancer

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Candidate Gene Evaluation In the past year, we have completed an extensive candidate gene study, genotyping 1355 candidate SNPs from 240 genes in a population-based, case-control study of 1308 PCa cases and 1267 controls (precise numbers varied by SNP based on genotyping success). Samples were collected by longtime collaborator Dr. Janet Stanford from the Fred Hutchison Cancer Research Center (FHCRC). We refer to this study throughout this document as the case-control study. Study subjects were incident PCa cases, while controls lacked a history of PCa at the time of ascertainment. Controls were matched for age, race and geographic region. All were residents in King County, Washington. Patients were identified via the Seattle-Puget Sound SEER Cancer Registry between 1993-1996 or 2002-2005. The Registry provides extensive diagnostic information including Gleason score, stage, diagnostic Prostate Specific Antigen (PSA) level and primary therapy. Among our many successes we: 1) demonstrated evidence for increased disease-risk associated with SNPs in MAOA (White et al., 2012), and CYP17 (Wright et al., 2010). 2) We showed roles for several genes, including selenoenzymes and SLCO transport genes in both risk and disease-related mortality (Geybels, 2012). 3) We validated published findings regarding a role for HOXB13 in PCa risk (Stott-Miller, 2012). 4) We showed risk associations for multiple SNPs in pathways including androgen metabolism (Kwon et al., 2012) and estrogen (Holt et al., 2013). Whole Exome Seqencing Our collaborative group also undertook a whole exome sequencing (WES) study of 80 affected and 11 unaffected men from 19 HPC (PROGRESS) families with aggressive and/or early onset disease (FitzGerald et al., 2013). Our initial analysis revealed two rare BTNL2 variants, rs41441651 and rs28362675, that segregate nearly perfectly with affected men from two of the 19 families. Interestingly, in the remaining 270 PROGRESS families (n = 819 PCa cases and 496 unaffecteds) the variants were found in 1.5% of affected men, but strikingly, no unaffected men (P = 0.0032 and 0.0070). Although rare in the population-based controls (0.9%), both variants were significantly associated with PCa risk when genotyped in the case-control study (n = 1,299 incident PCa cases and 1,141 controls), (OR = 2.3; 95% CI: 1.12-4.85 and OR = 2.1; 95% CI: 1.02-4.51) (FitzGerald et al., 2013). Consortia We are also active in several PCa consortia that have been very productive in the last year. These include: 1) PRACTICAL, which aims to validate published GWAS SNPs (Amin Al Olama et al., 2013); 2) ICPCG, which looks for hereditary prostate cancer (HPC) loci (Bailey-Wilson et al., 2012; Jin et al., 2012; Lu et al., 2012; Xu et al., 2013); and 3) the Northwest Prostate Cancer SPORE (Geybels, 2012; Holt et al., 2013; Kwon et al., 2012; White et al., 2012).