title: DNA Methyltransferase Gene Polymorphisms for Prediction of Radiation-Induced Skin Fibrosis after Treatment of Breast Cancer: A Multifactorial Genetic Approach.
abstract: OBJECTIVE
  This study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis.
  
  
  METHODS
  DNMT1rs2228611,DNMT3Ars1550117,DNMT3Ars7581217, andDNMT3Brs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC).
  
  
  RESULTS
  Kaplan-Meier curves showed significant differences amongDNMT1rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealedDNMT1rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). AddingDNMT1rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710).
  
  
  CONCLUSIONS
  DNMT1rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.
authors.affiliation: Department of Pharmaceutical Sciences and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), University of Piemonte Orientale, Novara, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Terrazzino
authors.affiliation: Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.|Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Deantonio
authors.affiliation: Department of Pharmaceutical Sciences and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), University of Piemonte Orientale, Novara, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cargnin
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Donis
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Pisani
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Masini
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Gambaro
authors.affiliation: Department of Pharmaceutical Sciences and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), University of Piemonte Orientale, Novara, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.affiliation: Department of Pharmaceutical Sciences and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), University of Piemonte Orientale, Novara, Italy.
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.affiliation: Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.|Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Krengli
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000150:complications* / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D015254:DNA Modification Methylases; D005260:Female; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D011836:Radiation Tolerance / Q000235:genetics; D012720:Severity of Illness Index; D012871:Skin Diseases / Q000175:diagnosis* / Q000209:etiology*
chemical_list: D015254:DNA Modification Methylases
keywords: Breast neoplasms; Fibrosis; Radiosensitivity; Single nucleotide polymorphism; Skin