Radiotherapy for breast cancer patients occasionally induces adverse effects. The adverse reactions to radiotherapy are caused by multiple factors, including individual genetic differences. The heterogeneity in normal tissue reactions may result from the combined effect of several different genetic alterations. Single nucleotide polymorphisms (SNPs) and derived haplotypes within multiple genes may be used to detect the genetic alterations related to the heterogeneity in normal tissue reactions. DNA was sampled from 397 Japanese breast cancer patients who qualified for breast-conserving radiotherapy. Using the NCI-CTC scoring system version 2, the patients were grouped according to adverse skin reactions at 3 months of starting radiotherapy (grade = 0, n = 230; grade ≥ 1, n = 167). Nine hundred and ninety-nine SNPs from 137 candidate genes for radiation susceptibility were genotyped, and haplotype associations between groups were assessed. Global haplotype association analysis (P < 0.05 and FDR < 0.005) indicated that estimated haplotypes in three loci were associated with the risk of adverse skin reactions. Comparison of risk haplotype to the most frequent haplotype in each locus showed haplotype CGATA(OR = 2.04; 95% CI, 1.19-3.52) and TGATG(OR = 5.05; 95% CI, 1.31-19.53) and TGAGG(OR = 12.89; 95% CI, 1.53-108.25) in TGFBI , CT in IL1A (OR = 1.83; 95% CI, 1.17-2.85), and AGT in GSTA4 (OR = 2.77; 95% CI, 1.23-6.22) had significantly greater adverse skin reactions risk.In conclusion, Individual radiosensitivity may be partly determined by combinations of these haplotypes in multiple loci. This would provide an understanding of the mechanisms underlying the genetic variation in radiation sensitivity or resistance among the population, and would show the possibility of prediction of the risk of adverse skin reactions prior to radiation therapy.10th Anniversary of Kazusa Arc International Symposium on Advanced Functional Genomic
