Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer

•Clinically significant radiotherapy toxicity can affect a number of breast cancer patients.•This genome-wide association study of 1,640 European-ancestry patients in the REQUITE cohort explored the relationship between common genetic variants (SNPs) and late radiotherapy toxicity.•Toxicity endpoints at 2-year follow-up included arm lymphoedema, breast atrophy, induration, nipple retraction, breast oedema and telangiectasia.•Eight SNPs reached genome-wide significance.•This study provides further evidence for significant association of common SNPs with distinct toxicity endpoints. Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. Quantile-quantile plots showed more associations with toxicity above the p