title: XRCC1 Polymorphism Associated With Late Toxicity After Radiation Therapy in Breast Cancer Patients.
abstract: OBJECTIVE
  To identify single-nucleotide polymorphisms (SNPs) in oxidative stress-related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy.
  
  
  METHODS
  Using a 2-stage design, 305 SNPs in 59 candidate genes were investigated in the discovery phase in 753 breast cancer patients from 2 prospective cohorts from Germany. The 10 most promising SNPs in 4 genes were evaluated in the replication phase in up to 1883 breast cancer patients from 6 cohorts identified through the Radiogenomics Consortium. Outcomes of interest were late skin toxicity and fibrosis of the breast, as well as an overall toxicity score (Standardized Total Average Toxicity). Multivariable logistic and linear regression models were used to assess associations between SNPs and late toxicity. A meta-analysis approach was used to summarize evidence.
  
  
  RESULTS
  The association of a genetic variant in the base excision repair gene XRCC1, rs2682585, with normal tissue late radiation toxicity was replicated in all tested studies. In the combined analysis of discovery and replication cohorts, carrying the rare allele was associated with a significantly lower risk of skin toxicities (multivariate odds ratio 0.77, 95% confidence interval 0.61-0.96, P=.02) and a decrease in Standardized Total Average Toxicity scores (-0.08, 95% confidence interval -0.15 to -0.02, P=.016).
  
  
  CONCLUSIONS
  Using a stage design with replication, we identified a variant allele in the base excision repair gene XRCC1 that could be used in combination with additional variants for developing a test to predict late toxicities after radiation therapy in breast cancer patients.
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Seibold
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Behrens
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Helmbold
authors.affiliation: Department of Oncology, Oncology Centre, Cambridge University Hospital NHS Foundation Trust, United Kingdom (UK).
authors.forename: Gillian
authors.initials: G
authors.lastname: Barnett
authors.affiliation: Department of Oncology, Oncology Centre, Cambridge University Hospital NHS Foundation Trust, United Kingdom (UK).
authors.forename: Charlotte
authors.initials: C
authors.lastname: Coles
authors.affiliation: Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Yarnold
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Talbot
authors.affiliation: Advanced Radiation Biology Research Program, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
authors.affiliation: Department of Radiation Oncology and Medical Physics, I.C.M. - Institut regional du Cancer Montpellier, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Azria
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: C Anne
authors.initials: CA
authors.lastname: Koch
authors.affiliation: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.affiliation: Department of Oncology, Oncology Centre, Cambridge University Hospital NHS Foundation Trust, University of Cambridge, Cambridge, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Burnet
authors.affiliation: The Institute of Cancer Research, Clinical Trials and Statistics Unit, Sutton, UK.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bliss
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Symonds
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Rattay
authors.affiliation: Advanced Radiation Biology Research Program, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tomo
authors.initials: T
authors.lastname: Suga
authors.affiliation: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NH.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kerns
authors.affiliation: Department of Radiation Oncology and Medical Physics, I.C.M. - Institut regional du Cancer Montpellier, Montpellier, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Bourgier
authors.affiliation: Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vallis
authors.affiliation: Department of Radiation Oncology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Sautter-Bihl
authors.affiliation: Clinic for Radiation Therapy and Radiation Oncology, St. Vincentius-Kliniken gAG, Karlsruhe, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Claßen
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Klinikum Ludwigshafen, Ludwigshafen am Rhein, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schnabel
authors.affiliation: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NH.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Rosenstein
authors.affiliation: Department of Radiation Oncology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.affiliation: Institute of Cancer Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Catharine M
authors.initials: CM
authors.lastname: West
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Odilia
authors.initials: O
authors.lastname: Popanda
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. Electronic address: j.chang-claude@dkfz.de.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001940:Breast / Q000473:pathology / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005355:Fibrosis / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011832:Radiation Injuries / Q000235:genetics* / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human