title: Common variants of GSTP1, GSTA1, and TGFβ1 are associated with the risk of radiation-induced fibrosis in breast cancer patients.
abstract: OBJECTIVE
  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, TGFβ1 C-509T, and TGFβ1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery.
  
  
  METHODS
  Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue--Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction--restriction 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 2-3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0-1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188-6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176-8.826; p = 0.022), and TGFβ1 T869C (OR 0.295; 95% CI, 0.090-0.964; p = 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2-3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2-3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553-12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671-27.447; p = 0.0003).
  
  
  CONCLUSIONS
  These results suggest that functional variations in genes involved in oxidative stress response and fibroblast proliferation may modulate the development of radiation-induced fibrosis in breast cancer patients. The results of the combined analysis support the notion that approaches based on the combination of different genetic markers have the potential to predict normal tissue responses.
authors.affiliation: DiSCAFF and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica, University of Piemonte Orientale Avogadro, Novara, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Terrazzino
authors.forename: Pierdaniele
authors.initials: P
authors.lastname: La Mattina
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Gambaro
authors.forename: Laura
authors.initials: L
authors.lastname: Masini
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Franco
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Marco
authors.initials: M
authors.lastname: Krengli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000473:pathology / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000532:radiotherapy* / Q000601:surgery; D049109:Cell Proliferation / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D005355:Fibrosis; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D016017:Odds Ratio; D018384:Oxidative Stress / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011832:Radiation Injuries / Q000235:genetics* / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics*; D012044:Regression Analysis; D012189:Retrospective Studies; D012306:Risk; D040521:Subcutaneous Tissue / Q000473:pathology / Q000528:radiation effects*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; C508960:TGFB1 protein, human; C495901:TP53 protein, human; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D052250:Nitric Oxide Synthase Type III; C484555:GSTA1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase