title: Limited family structure and BRCA gene mutation status in single cases of breast cancer.
abstract: BACKGROUND
  An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression.
  
  
  OBJECTIVE
  To determine if BRCA gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models.
  
  
  METHODS
  A total of 1543 women seen at US high-risk clinics for genetic cancer risk assessment and BRCA gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers.
  
  
  METHODS
  The main outcome measure was whether family structure, assessed from multigenerational pedigrees, predicts BRCA gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were generated.
  
  
  RESULTS
  Family structure was limited in 153 cases (50%). BRCA gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer.
  
  
  CONCLUSIONS
  Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.
authors.affiliation: Department of Clinical Cancer Genetics, City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA. jweitzel@coh.org
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Lagos
authors.forename: Carey A
authors.initials: CA
authors.lastname: Cullinane
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gambol
authors.forename: Julie O
authors.initials: JO
authors.lastname: Culver
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Blazer
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Palomares
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Lowstuter
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: MacDonald
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005191:Family Characteristics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D011336:Probability; D012042:Registries; D018570:Risk Assessment