Candidate Gene Evaluation In the past two years, we completed an extensive candidate gene study, genotyping 1355 candidate SNPs from 240 genes in a population-based, case-control study of 1308 prostate cancer (PCa_ cases and 1267 controls. This work was done in collaboration with longtime collaborator Dr. Janet Stanford from the Fred Hutchison Cancer Research Center (FHCRC) who lead the epidemiology components in addition to ascertaining the managing the 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. We recent completed a validation study of genes with hypermethlated regions associated with prostate cancer. The Infinium HumanMethylation450 BeadChip was used to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence (Stott-Miller et al., 2014). We also studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). We evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. Only GPX1 was associated with overall PCa risk. SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade (Geybels et al., 2013). Finally, we participated in a meta and pooled analysis of published and unpublished case-control studies was performed to evaluate the association of CYP17 (rs743572) and CYP3A4 (rs2740574) polymorphisms and prostate cancer (PCa) in men from the USA, Caribbean, and Africa. We found that overall, the CYP17 heterozygous and homozygous variants were not associated with PCa, but they confer a 60% increased risk of PCa in a sub-group analysis restricted to African-American men (T/C + C/C, OR: 1.6, 95% CI: 1.1-2.4). The pooled analysis suggests that after adjusting for study, age, PSA, and family history of PCa, CYP17 was associated with PCa for men of African ancestry (Adjusted OR: 3.5, 95% CI: 1.2-10.0). 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). This study is continuing with an expanded data set this year. 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;2) ICPCG, which looks for hereditary prostate cancer (HPC) loci;and 3) the Northwest Prostate Cancer SPORE. We examined the role of HOXB13 as part of a PRACTICAL study, a gene which has been implicated in prostate cancer (Saunders et al., 2014). We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk. We worked with the ICPCG to 14 loci in 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees (Teerlink et al., 2014). 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.
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