title: Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study.
abstract: BACKGROUND
  Radiation exposure at a young age is one of the strongest risk factors for breast cancer. Germline mutations in genes involved in the DNA-damage repair pathway (DDRP) may render women more susceptible to radiation-induced breast cancer.
  
  
  METHODS
  We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour.
  
  
  RESULTS
  We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Those patients had an odds ratio of 2.51 (95% confidence interval 1.03 to 6.10; p = 0.049) of developing radiation-induced breast cancer, in comparison with non-carriers.
  
  
  CONCLUSIONS
  This study shows that carriers of germline mutations in a DDRP gene have an increased risk of developing (contralateral) breast cancer after radiotherapy; that is, over and above the risk associated with their carrier status. The increased risk indicates that knowledge of germline status of these DDRP genes at the time of breast cancer diagnosis may have important implications for the choice of treatment.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. a.broeks@nki.nl
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Linde M
authors.initials: LM
authors.lastname: Braaf
authors.forename: Angelina
authors.initials: A
authors.lastname: Huseinovic
authors.forename: Anke
authors.initials: A
authors.lastname: Nooijen
authors.forename: Jos
authors.initials: J
authors.lastname: Urbanus
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Russell
authors.forename: Flora E
authors.initials: FE
authors.lastname: Van Leeuwen
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Van 't Veer
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000175:diagnosis* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases