Prognostic impact of genetic variation in steroidogenic enzymes in advanced stage prostate cancer.

Abstract

e16605 Background: Extragonadal androgen biosynthesis controls tumor growth and impacts survival in men with metastatic castration-resistant prostate cancer (mCRPC). We investigated the associations between single nucleotide polymorphisms (SNPs) in CYP17A1 and HSD3β2, genes that code for key enzymesinvolved in sex steroid pathways with survival in men with advanced prostate cancer. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of mCRPC patients. Six SNPs in the two genes (CYP17A1 and HSD3β2 ) with minor allele frequency (MAF) ≥ 0.05 were identified using a haplotype-based tagging algorithm, providing 100% coverage of the common genetic variations. Genotyping was carried out on the MassARRAY iPLEX platform. The adjusted α-level after correcting for multiple testing was 0.010. The outcome measure of interest was overall survival, defined as time from initial diagnosis to death or the date of last follow-up. Multivariable Cox regression models were used to assess the association between genetic variation and overall survival. Effect measures were expressed as hazard ratios per minor allele. Results: We successfully genotyped 328 men with prostate cancer. The median age at diagnosis was 64 years (Range 43-89). After a median follow-up time of 8 years (0 - 38), 184/328 men (56%) had died. The genetic variant rs4919685 in CYP17A1 (MAF = 0.29) was associated with increased mortality (HR 1.39, 95% CI 1.10-1.75, p = 0.005), after adjusting for age, stage, grade, and prostate-specific antigen at the time of diagnosis. No SNP in HSD3β2 was associated with the outcome of interest. Conclusions: Genetic variation in CYP17A1, a gene that encodes key sex steroidogenic enzymes has demonstrated prognostic significance in prostate cancer. These promising results warrant validation in a larger independent cohort.