Haplotype-based analysis of genes associated with risk of adverse skin reactions after radiotherapy in breast cancer patients.

Abstract

To identify haplotypes of single nucleotide polymorphism markers associated with the risk of early adverse skin reactions (EASRs) after radiotherapy in breast cancer patients. DNA was sampled from 399 Japanese breast cancer patients who qualified for breast-conserving radiotherapy. Using the National Cancer Institute-Common Toxicity Criteria scoring system, version 2, the patients were grouped according to EASRs, defined as those occurring within 3 months of starting radiotherapy (Grade 1 or less, n = 290; Grade 2 or greater, n = 109). A total of 999 single nucleotide polymorphisms from 137 candidate genes for radiation susceptibility were genotyped, and the haplotype associations between groups were assessed. The global haplotype association analysis (p < 0.05 and false discovery rate < 0.05) indicated that estimated haplotypes in six loci were associated with EASR risk. A comparison of the risk haplotype with the most frequent haplotype in each locus showed haplotype GGTT in CD44 (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.07-4.43) resulted in a significantly greater EASR risk. Five haplotypes, CG in MAD2L2 (OR = 0.55; 95% CI, 0.35-0.87), GTTG in PTTG1 (OR = 0.48; 95% CI, 0.24-0.96), TCC (OR = 0.48; 95% CI, 0.26-0.89) and CCG (OR = 0.50; 95% CI, 0.27-0.92) in RAD9A, and GCT in LIG3 (OR = 0.46; 95% CI, 0.22-0.93) were associated with a reduced EASR risk. No significant risk haplotype was observed in REV3L. Individual radiosensitivity can be partly determined by these haplotypes in multiple loci. Our findings may lead to a better understanding of the mechanisms underlying the genetic variation in radiation sensitivity and resistance among breast cancer patients.