Common variants of GSTP1, GSTA1, and TGFβ1 are associated with the risk of radiation-induced fibrosis in breast cancer patients

Purpose: To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFb1 C-509T, and TGFb1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery. Methods and Materials: Subcutaneous fibrosis was scored according to the Late Effects of Normal TissuedSubjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reactiondrestriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. The association between genetic variants and the risk of moderate to severe fibrosis was evaluated by binary logistic regression analysis. Results: Two hundred thirty-seven patients were available for the analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis (Grade 2e3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0e1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188e6.393; p Z 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176e8.826; p Z 0.022), and TGFb1 T869C (OR 0.295; 95% CI, 0.090e0.964; p Z 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2e3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2e3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553 e12.551, p Z 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671e27.447; p Z 0.0003).