The identification of haplotypes in radiosensitive genes associated with risk for adverse skin reactions following radiotherapy in breast cancer patients.

The goal of radiation therapy in cancer treatment is to achieve a personalized, uncomplicated, loco-regional control. For this, it is of critical importance to have a precise knowledge of the tumoricidal dose for each target tumor and the tolerance doses of normal tissues for each patient. Single nucleotide polymorphisms (SNPs) and derived haplotypes within multiple genes may explain the genetic basis for variations in the adverse reactions after radiotherapy for cancer patients. Using DNA samples collected from 184 Japanese breast cancer patients who qualified for breast-conserving surgery and radiotherapy, we genotyped 905 SNPs from 127 candidate genes for radiation susceptibility. These genes were mainly selected from our gene expression analyses of cultured human cell lines and mouse strains that had exhibited variable radiosensitivities. The SNPs in the candidate genes were selected from jSNP and dbSNP databases and their allele frequencies were examined using 133 healthy controls. The adverse skin reactions were clinically graded according to the National Cancer Institute Common Toxicity Criteria scoring system. Of all 905 SNPs tested, approximately 64% were polymorphic in this cohort of patients. Significant differences were observed in genotype frequencies between the grade 0+1 (n=140) and the grade 2+3 (n=44) groups of skin reactions among the breast cancer patients within 3 months after starting radiotherapy for 24 SNPs in 12 candidate gene loci. Forty-four haplotypes were generated in 7 of the above loci and 4 of these haplotypes were associated with the risk of the adverse skin reactions. These data suggest that the tagged SNPs in the loci may be useful in predicting the risk of adverse reactions following radiation treatment.ASHG 55th Annual Meetin