title: Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families.
abstract: A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.
authors.affiliation: Department of Medicine, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 192, New York, NY 10021, USA.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Saloustros
authors.forename: Nichole A L
authors.initials: NA
authors.lastname: Hansen
authors.forename: Alice E
authors.initials: AE
authors.lastname: Schluger
authors.forename: Noah D
authors.initials: ND
authors.lastname: Kauff
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robson
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D005260:Female; D018703:Founder Effect; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009519:New York City / Q000453:epidemiology; D010051:Ovarian Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human