Genetic variants and prostate cancer risk: Candidate replication and exploration of viral restriction genes

Abstract

The genetic variants underlying the strong heritable component ofprostate cancer remain largely unknown. Genome-wide association studies ofprostate cancer have yielded several variants that have significantly replicated across studies, predominantly in cases unselected for family history of prostate cancer. Additional candidate gene variants have also been proposed, many evaluated within familial prostate cancer study populations. Such variants hold great potential value for risk stratification, particularly for early-onset or aggressive prostate cancer, given the comorbidities associated with current therapies. Here, we investigate a Caucasian study population of523 independent familial prostate cancer cases and 523 agematched controls without a personal or family history ofprostate cancer. We replicate identified associations at genome-wide association study loci 8q24, 11q13, and 2p15 (P = 2.9 x 10 -4 to P = 4.7 x 10-5), showing study population power. We also find evidence to support reported associations at candidate genes RNASEL, EZH2, and NKX3-1 (P = 0.031 to P = 0.0085). We further explore a set of candidate genes related to RNASEL and to its role in retroviral restriction, identifying nominal associations at XPR1 and RBM9. The effects at 8q24 seem more pronounced for those diagnosed at an early age, whereas at 2p15 and RNASEL the effects were more pronounced at a later age. However, these trends did not reach statistical significance. The effects at 2p15 were statistically significantly more pronounced for those diagnosed with aggressive disease. Copyright © 2009 American Association for Cancer Research.