Two susceptibility loci identified for prostate cancer aggressiveness.

Berndt SI1, Wang Z2, Yeager M2, Alavanja MC1, Albanes D1, Amundadottir L1, Andriole G3, Beane Freeman L1, Campa D4, Cancel-Tassin G5, Canzian F6,Cornu JN1, Cussenot O5, Diver WR7, Gapstur SM7, Grönberg H8, Haiman CA9, Henderson B9, Hutchinson A10, Hunter DJ11, Key TJ12, Kolb S13, Koutros S1,Kraft P11, Le Marchand L14, Lindström S11, Machiela MJ1, Ostrander EA15, Riboli E16, Schumacher F9, Siddiq A17, Stanford JL18, Stevens VL7, Travis RC12,Tsilidis KK19, Virtamo J20, Weinstein S1, Wilkund F8, Xu J21, Lilly Zheng S21, Yu K1, Wheeler W22, Zhang H1; African Ancestry Prostate Cancer GWAS Consortium, Sampson J1, Black A1, Jacobs K1, Hoover RN1, Tucker M1, Chanock SJ1.

Abstract

Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.