title: Study design: evaluating gene-environment interactions in the etiology of breast cancer - the WECARE study.
abstract: BACKGROUND
  Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.
  
  
  METHODS
  To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.
  
  
  CONCLUSIONS
  Our study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhanced our ability to detect radiation-genotype interactions.
authors.affiliation: Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA. jonine.bernstein@mssm.edu
authors.forename: Jonine L
authors.initials: JL
authors.lastname: Bernstein
authors.forename: Bryan
authors.initials: B
authors.lastname: Langholz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.forename: Marilyn
authors.initials: M
authors.lastname: Stovall
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Malone
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Jørgen H
authors.initials: JH
authors.lastname: Olsen
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Roy E
authors.initials: RE
authors.lastname: Shore
authors.forename: John D
authors.initials: JD
authors.lastname: Boice
authors.forename: Gertrud S
authors.initials: GS
authors.lastname: Berkowitz
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: Susan A
authors.initials: SA
authors.lastname: Smith
authors.forename: Barry S
authors.initials: BS
authors.lastname: Rosenstein
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics / Q000532:radiotherapy; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D003043:Cocarcinogenesis; D004268:DNA-Binding Proteins; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D019047:Phantoms, Imaging; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011878:Radiotherapy / Q000009:adverse effects*; D011879:Radiotherapy Dosage; D012042:Registries / Q000706:statistics & numerical data; D012107:Research Design; D016037:Single-Blind Method; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases