Rider, D. R.

44 Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We successfully genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow-up of 1.8 years (IQ range: 0.8–3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table . Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers. [Table: see text] No significant financial relationships to disclose.

14 Background: We evaluated the association of germline variation in genes regulating hormonal pathways with duration of treatment response in prostate cancer patients receiving ADT, focusing on genes in the androgen biosynthesis (the C4 Δ; C5 Δ; C21 CYP pathways and the alternate “backdoor pathway”) and metabolism pathways. Methods: We successfully genotyped 747 single nucleotide polymorphisms (SNPs) from 84 genes in a cohort of 304 patients with advanced prostate cancer who progressed on ADT. Tagging SNPs with a minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. The primary endpoint was time to ADT failure, and we conducted a gene-level test (principal components), along with individual SNP level tests adjusted for patient age and Gleason score. To account for multiple testing, we calculated the false discovery rate (FDR), and FDRs of 0.10 were considered noteworthy. Results: The median age of the cohort at ADT failure was 72 years (range 65-78 years), and the overall median time to ADT failure was 3.21 years (IQ [25-75]: 1.54-6.20 years). At the gene level, TRMT11 (tRNA methyltransferase 11 homologue) showed the strongest association with time to ADT failure (p<0.0008; adjusted p-value for FDR-0.068). Two of four TRMT11 tag SNPs were associated with time to ADT failure. The first was the intronic SNP rs1268121 (A>G) with a MAF of 15%, for which there was a positive association of median time to ADT failure with the number of variant alleles (p=0.023): 3.1 years for 0, 4.1 years for 1, and 5.9 years for 2 variant alleles. The second was the SNP rs6900796 (A>G) in the 3' untranscribed region with a MAF of 49%, for which the median time to ADT failure was 2.6 years for 0, 2.5 years for 1, and 3.8 years for 2 variant alleles (p=0.023). Four additional genes showed an association with ADT response at the p<0.10 level, including LOC390956, PRMT3, SLC7A6OS, and WBSCR22, although all FDRs were >0.95. Conclusions: Variation in TRMT11 was associated with time to ADT failure. Confirmation of these findings in an independent cohort is needed. No significant financial relationships to disclose.