A validation study of genes and polymorphisms associated with radiation toxicity: preliminary results of the RAPPER study


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Gillian Barnett1,Catharine West3,Caroline Baynes1,Craig Luccarini1,Don Conroy1,Charlotte Coles2,Rebecca Elliott1,Neil Burnet2,Paul Pharoah1,Alison Dunning1
1Strangeways Research Laboratory, Cambridge, United Kingdom,2Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom,3University of Manchester, Christie Hospital, Manchester, United Kingdom

Background

RAPPER is a large radiogenomics study designed to test for associations between common genetic variation and late radiation toxicity. This study aimed to evaluate previously reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes encoding DNA repair proteins, antioxidant enzymes and cytokines such as TGFB1.

Method

96 SNPs were genotyped in 943 breast cancer patients who had received adjuvant radiotherapy. Two-year toxicity was assessed using clinical assessment, photographs and patient questionnaires. The relationship between genotype and radiation toxicity, reported by individual endpoints and by a purposely-developed score - the standardised total average toxicity (STAT) score was assessed. Multivariate analysis including all patient- and treatment-related risk factors thought to affect toxicity was performed.

Results

Most previously reported associations were not confirmed in this large study, but some positive associations were found. The minor alleles of MRE11 SNPs rs569143 & rs2155209 and ATM SNP rs1800057 (P1054R) were associated with differences in overall toxicity (P= 0.001, 0.0009 and 0.003 respectively). The rare alleles of HIF1A SNP rs230113, XRCC3 SNP rs1799794 and rs1805386 in LIG4 were associated with increased breast shrinkage (P=0.003), pigmentation (P=0.007) and poorer overall cosmesis (P=0.009) respectively. The minor allele of XRCC1 SNP rs2293036 was associated with decreased risk of telangiectasia. The effect sizes associated with each SNP were small, and none of the results were significant after correction for multiple testing.

Conclusion

Reported candidate gene SNP associations for radiation toxicity have proved difficult to confirm. Three of the seven results reported in this study were in keeping with previous associations. Genome Wide Association Studies (GWAS) are more effective than candidate gene studies at identifying common genetic variants associated with traits and diseases. An international Radiogenomics Consortium has been established to raise the quality of SNP association studies and facilitate the eventual pooling of data for an adequately powered GWAS.