title: Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer.
abstract: The BRCA1 gene on human chromosome 17q21 is responsible for an autosomal dominant syndrome of inherited early onset breast/ovarian cancer. It is estimated that women harboring a germline BRCA1 mutation incur an 85% lifetime risk of breast cancer and a greatly elevated risk of ovarian cancer. The BRCA1 gene has recently been isolated and mutations have been found in the germline of affected individuals in linked families. Previous studies of loss of heterozygosity (LOH) in breast tumors have been carried out on sporadic tumors derived from individuals without known linkage to BRCA1 and on tumors from linked families. Loss of large regions of chromosome 17 has been observed, but these LOH events could not be unequivocally ascribed to BRCA1. We have studied 28 breast and 6 ovarian tumors from families with strong evidence for linkage between breast cancer and genetic markers flanking BRCA1. These tumors were examined for LOH using genetic markers flanking and within BRCA1, including THRA1, D17S856, EDH17B1, EDH17B2, and D17S183. Forty-six percent (16/34) of tumors exhibit LOH which includes BRCA1. In 8 of 16 tumors the parental origin of the deleted allele could be determined by evaluation of haplotypes of associated family members; in 100% of these cases, the wild-type allele was lost. In some of these families germline mutations in BRCA1 have been determined; analyses of tumors with LOH at BRCA1 have revealed that only the disease-related allele of BRCA1 was present. These data strongly support the hypothesis that BRCA1 is a tumor suppressor gene.
authors.affiliation: Departments of Internal Medicine, Pathology, and Human Genetics, and the Human Genome Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Merajver
authors.forename: T S
authors.initials: TS
authors.lastname: Frank
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: T M
authors.initials: TM
authors.lastname: Pham
authors.forename: K A
authors.initials: KA
authors.lastname: Calzone
authors.forename: P
authors.initials: P
authors.lastname: Bennett-Baker
authors.forename: J
authors.initials: J
authors.lastname: Chamberlain
authors.forename: J
authors.initials: J
authors.lastname: Boyd
authors.forename: J E
authors.initials: JE
authors.lastname: Garber
authors.forename: F S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D017668:Age of Onset; D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D005190:Family; D005260:Female; D019398:Genes, BRCA1; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D008126:Lod Score; D019656:Loss of Heterozygosity; D008297:Male; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D017384:Sequence Deletion
chemical_list: D019313:BRCA1 Protein; D005819:Genetic Markers