Meta-Analysis of Genome-Wide Association Studies (GWAS) of Late Toxicity in 3,874 Men Treated with Radiation for Prostate Cancer

Abstract

Late toxicity following prostate cancer radiotherapy negatively impacts quality of life and can be dose-limiting. Radiosensitivity is a genetic trait, and identification of single nucleotide polymorphisms (SNPs) associated with toxicity could uncover novel radiobiology pathways and contribute to precision cancer care. The largest study to date meta-analyzed data from 1,564 men with prostate cancer and identified two risk SNPs. This expanded study added new cohorts to greatly increase the sample to 3,874 men with the aim of identifying new toxicity risk SNPs and validating previously identified SNPs. A GWAS meta-analysis was performed with six independent cohorts of men treated with radiotherapy for prostate cancer: RAPPER (n=2,010), RADIOGEN (n=658), GenePARE (n=495), UGhent (n=311), CCI-BT (n=252), and CCI-EBRT (n=148). Four toxicities were assessed prospectively from 6 months after radiotherapy and harmonized to a common scale: increased urinary frequency, decreased urine stream, hematuria, and rectal bleeding. Germline DNA was genotyped using genome-wide arrays. Imputation generated a uniform set of ∼7 million SNPs (frequency in Europeans >4%) across cohorts. Cox proportional hazards regression tested association between each SNP and time to first occurrence of grade 2 or worse toxicity within each cohort. Individual cohort results were combined using inverse variance weighted fixed-effects meta-analysis. Novel SNP-toxicity associations were considered significant if they had meta-p-value <5x10-8. Bayesian False Discovery Probability (BFDP) provided an additional measure of confidence. Five new risk loci for late toxicity were identified in 3,874 prostate cancer patients: rs17055178 (HR 1.98; 95%CI 1.60 to 2.44; p=2.4x10-10; BFDP <1%) and rs9644474 (HR 0.47; 95%CI 0.36 to 0.62; p=4.3x10-8; BFDP 10%) associated with rectal bleeding; rs10969913 (HR 3.82; 95%CI 2.50 to 5.83; p=6.2x10-10; BFDP 1.6%) with decreased urine stream; rs11122573 (HR 1.89; 95%CI 1.50 to 2.38; p=2.3x10-8; BFDP 5.7%) and rs139882217 (HR 4.83; 95%CI 2.73 to 8.52; p=2.7x10-8; BFDP 69%) with hematuria. Previously published risk SNPs showed consistent associations in the cohorts not included in prior discovery GWAS: rs1801516 in ATM associated with overall toxicity (ß=0.05; 95%CI 0.01 to 0.09; p=0.016), rs17599026 in KDM3B associated with 2yr prevalence of increased urinary frequency (OR 1.27; 95%CI 0.95 to 1.70; p=0.10), rs7720298 in DNAH5 associated with 2yr prevalence of decreased urine stream (OR 1.26; 95%CI 0.94 to 1.70; p=0.13). A locus in TANC1 showed replication in some, but not all, new cohorts and warrants further investigation. This largest GWAS to date identified novel risk SNPs and replicated previously identified SNPs. Further expansion of cohorts will uncover additional SNPs and allow development of risk models. Such models can be tested in clinical trials aimed at stratification of cancer patients based on toxicity risk profile.