Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer.
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Jandu Harkeran K, Veal Colin D, Fachal Laura, Luccarini Craig, Aguado-Barrera Miguel E, Altabas Manuel, Azria David, Baten Adinda, Bourgier Celine, Bultijnck Renée, Colciago Riccardo R, Farcy-Jacquet Marie-Pierre, Chang-Claude Jenny, Choudhury Ananya, Dunning Alison, Elliott Rebecca M, Green Sheryl, Gutiérrez-Enríquez Sara, Herskind Carsten, Lambrecht Maarten, Monten Christel, Rancati Tiziana, Reyes Victoria, Rosenstein Barry S, De Ruysscher Dirk, Carmen De Santis Maria, Seibold Petra, Sperk Elena, Veldwijk Marlon, Paul Symonds R, Stobart Hilary, Taboada-Valladares Begoña, Vega Ana, Veldeman Liv, Webb Adam J, Weltens Caroline, West Catharine M, Rattay Tim, Talbot Christopher J, REQUITE consortium
Аннотация
MATERIALS AND METHODS: 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.
RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level.
CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.