A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

作者：Barnett Gillian C^*; Thompson Deborah; Fachal Laura; Kerns Sarah; Talbot Chris; Elliott Rebecca M; Dorling Leila; Coles Charlotte E; Dearnaley David P; Rosenstein Barry S; Vega Ana; Symonds Paul; Yarnold John; Baynes Caroline; Michailidou Kyriaki; Dennis Joe; Tyrer Jonathan P; Wilkinson Jennifer S; Gomez Caamano Antonio; Tanteles George A; Platte Radka; Mayes Rebecca; Conroy Don; Maranian Mel; Luccarini Craig; Gulliford Sarah L; Sydes Matthew R; Hall Emma

来源：Radiotherapy and Oncology, 2014, 111(2): 178-185.

DOI：10.1016/j.radonc.2014.02.012

• Radiotherapy
• Late toxicity
• Adverse effects
• Genetics
• Genome-wide association scan

Background and purpose: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2 years after radiotherapy. %26lt;br%26gt;Materials and methods: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. %26lt;br%26gt;Results: Quantile-quantile plots show more associations at the P %26lt; 5 x 10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. %26lt;br%26gt;Conclusions: This largest GWAS to date provides evidence of true association between common genetic. variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

• 出版日期2014-5