A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1

Nature Genetics

(2014)

doi:10.1038/ng.3020

Received: 04 November 2013
Accepted: 05 June 2014
Published online: 29 June 2014

There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity¹. However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype², which could emerge years after the completion of treatment³. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK⁴ and 368 cases from North America⁵. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity = 6.85 × 10⁻⁹, odds ratio (OR) = 6.61, 95% confidence interval (CI) = 2.23–19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity = 2.08 × 10⁻⁴, OR = 6.17, 95% CI = 2.25–16.95;Pcombined = 4.16 × 10⁻¹⁰). The inclusion of the third cohort gave unadjusted Pcombined = 4.64 × 10⁻¹¹. These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.