Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases

• DOI: 10.1007/s00439-015-1534-9
• Publication Date: 2015-02-25T07:50:34Z
• Authors: Brian T. Helfand; Kimberly A. Roehl; Phillip R. Cooper; Barry B. McGuire; Liesel M. Fitzgerald; Geraldine Cancel-...; Jean-Nicolas Cornu; Scott Bauer; Erin L. Van Blarigan; Xin Chen; David Duggan; Elaine A. Ostrander; Mary Gwo-Shu; Zuo-Feng Zhang; Shen-Chih Chang; Somee Jeong; Elizabeth T. H. F...; Gary Smith; James L. Mohler; Sonja I. Berndt; Shannon K. McDonnell; Rick Kittles; Benjamin A. Rybicki; Matthew Freedman; Philip W. Kantoff; Mark Pomerantz; Joan P. Breyer; Jeffrey R. Smith; Timothy R. Rebbeck; Dan Mercola; William B. Isaacs; Fredrick Wiklund; Olivier Cussenot; Stephen N. Thibodeau; Daniel J. Schaid; Lisa Cannon-Albright; Kathleen A. Cooney; Stephen J. Chanock; Janet L. Stanford; June M. Chan; John Witte; Jianfeng Xu; Jeannette T. Bensen; Jack A. Taylor; William J. Catalona
• Keywords: Urologic Diseases; Adult; Male; 0301 basic medicine; Aging; Clinical Sciences; Oncology and Carcinogenesis; 610; Polymorphism, Single Nucleotide; Paediatrics and Reproductive Medicine; Cohort Studies; 03 medical and health sciences; Complementary and Alternative Medicine; Clinical Research; Risk Factors; 80 and over; Genetics; 2.1 Biological and endogenous factors; Humans; Genetic Predisposition to Disease; Neoplasm Invasiveness; Polymorphism; Genetic Association Studies; Cancer; Aged; Genetics & Heredity; Aged, 80 and over; Biomedical and Clinical Sciences; Prevention; Prostate Cancer; Human Genome; Prostatic Neoplasms; Single Nucleotide; Biological Sciences; Middle Aged; National Cancer Institute (U.S.); United States; 3. Good health; Reproductive medicine

Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤ 6, 7, ≥ 8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69-0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68-0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58-0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54-0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness.