title: Common European Mitochondrial Haplogroups in the Risk for Radiation-induced Subcutaneous Fibrosis in Breast Cancer Patients.
abstract: The contribution of mitochondrial DNA (mtDNA) variations to clinical radiosensitivity is largely unknown. In the present study, we evaluated the association between mtDNA haplogroups and the risk of radiation-induced subcutaneous fibrosis after postoperative radiotherapy in breast cancer patients.
  
  
  
  Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale in 286 Italian breast cancer patients who received radiotherapy after breast-conserving surgery. Eight mtDNA single nucleotide polymorphisms that define the nine major haplogroups in the European population were determined by polymerase chain reaction restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood.
  
  
  
  In a Kaplan-Meier analysis evaluated by the Log-rank test, carriers of haplogroup H were found to be at lower risk of grade ≥2 subcutaneous fibrosis (P = 0.018) compared with all other haplotypes combined. In the multivariate Cox regression analysis adjusted for clinical factors (body mass index, breast diameter, adjuvant treatment, dose per fraction, radiation type and acute skin toxicity), haplogroup H emerged as a protective factor for moderate to severe radiation-induced fibrosis at a nominal significance level (hazard ratio: 0.50, 95% confidence interval 0.27-0.92, P = 0.027), which did not survive correction for multiple testing.
  
  
  
  Our results suggest a protective effect of the mitochondrial haplogroup H in the development of radiation-induced fibrosis in breast cancer patients. However, the loss of statistical significance after correction for multiple comparisons and the lack of an independent validation cohort make our findings preliminary, requiring further confirmation in large-scale prospective studies.
authors.affiliation: Department of Pharmaceutical Sciences and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), University of Piemonte Orientale, Novara, Italy.
authors.forename: S
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: L
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: S
authors.initials: S
authors.lastname: Cargnin
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Donis
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Pisani
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Masini
authors.affiliation: Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy.
authors.forename: G
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: P L
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: A 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. Electronic address: marco.krengli@med.unipmn.it.
authors.forename: M
authors.initials: M
authors.lastname: Krengli
mesh_terms: D001940:Breast / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000532:radiotherapy*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005355:Fibrosis / Q000175:diagnosis / Q000209:etiology*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011832:Radiation Injuries / Q000175:diagnosis / Q000209:etiology*; D011878:Radiotherapy / Q000009:adverse effects*; D012307:Risk Factors; D044465:White People
chemical_list: D004272:DNA, Mitochondrial
keywords: Breast cancer; mitochondrial DNA; normal tissue radiosensitivity; radiotherapy; subcutaneous fibrosis