title: Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study.
abstract: BACKGROUND
  Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset.
  
  
  METHODS
  92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2.
  
  
  RESULTS
  None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance.
  
  
  CONCLUSIONS
  We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed.
  
  
  BACKGROUND
  Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.
authors.affiliation: University of Cambridge, Department of Oncology, Cambridge, UK. gillbarnett@doctors.org.uk
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Barnett
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Coles
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Elliott
authors.forename: Caroline
authors.initials: C
authors.lastname: Baynes
authors.forename: Craig
authors.initials: C
authors.lastname: Luccarini
authors.forename: Don
authors.initials: D
authors.lastname: Conroy
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Wilkinson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tyrer
authors.forename: Vivek
authors.initials: V
authors.lastname: Misra
authors.forename: Radka
authors.initials: R
authors.lastname: Platte
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gulliford
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.forename: Emma
authors.initials: E
authors.lastname: Hall
authors.forename: Søren M
authors.initials: SM
authors.lastname: Bentzen
authors.forename: David P
authors.initials: DP
authors.lastname: Dearnaley
authors.forename: Neil G
authors.initials: NG
authors.lastname: Burnet
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Catharine M L
authors.initials: CM
authors.lastname: West
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000235:genetics* / Q000473:pathology; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D006113:United Kingdom