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

Research output: Contribution to journalArticle

  • External authors:
  • Gillian C. Barnett
  • Deborah Thompson
  • Laura Fachal
  • Sarah Kerns
  • Chris Talbot
  • Rebecca M. Elliott
  • Leila Dorling
  • Charlotte E. Coles
  • David P. Dearnaley
  • Barry S. Rosenstein
  • Ana Vega
  • Paul Symonds
  • John Yarnold
  • Caroline Baynes
  • Kyriaki Michailidou
  • Joe Dennis
  • Jonathan P. Tyrer
  • Jennifer S. Wilkinson
  • Antonio Gómez-Caamaño
  • George A. Tanteles
  • Radka Platte
  • Rebecca Mayes
  • Don Conroy
  • Mel Maranian
  • Craig Luccarini
  • Sarah L. Gulliford
  • Matthew R. Sydes
  • Emma Hall
  • Joanne Haviland
  • Vivek Misra
  • Jennifer Titley
  • Søren M. Bentzen
  • Paul D P Pharoah
  • Neil G. Burnet
  • Alison M. Dunning

Abstract

Background and purpose This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2 years after radiotherapy. 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. Results Quantile-quantile plots show more associations at the P <5 × 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. 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. © 2014 Elsevier Ireland Ltd. All rights reserved.

Bibliographical metadata

Original languageEnglish
Pages (from-to)178-185
Number of pages7
JournalRadiotherapy and Oncology
Volume111
Issue number2
DOIs
Publication statusPublished - 2014