title: Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers.
abstract: Germline alterations of BRCA1 result in susceptibility to breast and ovarian cancer. The protein encoded by BRCA1 interacts in vivo with the BRCA1-associated RING domain (BARD1) protein. Accordingly, BARD1 is likely to be a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. We have now determined the genomic structure of BARD1 and performed a mutational analysis of 58 ovarian tumors, 50 breast tumors and 60 uterine tumors. Seven polymorphisms were detected within the 2.34 kb coding sequence of BARD1 . Somatically acquired missense mutations were observed in one breast carcinoma and one endometrial tumor; in at least one of these cases, tumor formation was accompanied by loss of the wild-type BARD1 allele, following the paradigm for known tumor suppressor genes. In addition, a germline alteration of BARD1 was identified in a clear cell ovarian tumor (Gln564His); again, loss of the wild-type BARD1 allele was observed in the malignant cells of this patient. The Gln564His patient was also diagnosed with two other primary cancers: a synchronous lobular breast carcinoma and a stage IA clear cell endometrioid cancer confined to an endometrial polyp 6 years earlier. These findings suggest an occasional role for BARD1 mutations in the development of sporadic and hereditary tumors.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Thai
authors.forename: F
authors.initials: F
authors.lastname: Du
authors.forename: J T
authors.initials: JT
authors.lastname: Tsan
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.forename: A
authors.initials: A
authors.lastname: Phung
authors.forename: M A
authors.initials: MA
authors.lastname: Spillman
authors.forename: H F
authors.initials: HF
authors.lastname: Massa
authors.forename: C Y
authors.initials: CY
authors.lastname: Muller
authors.forename: R
authors.initials: R
authors.lastname: Ashfaq
authors.forename: J M
authors.initials: JM
authors.lastname: Mathis
authors.forename: D S
authors.initials: DS
authors.lastname: Miller
authors.forename: B J
authors.initials: BJ
authors.lastname: Trask
authors.forename: R
authors.initials: R
authors.lastname: Baer
authors.forename: A M
authors.initials: AM
authors.lastname: Bowcock
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D018262:Adenocarcinoma, Clear Cell / Q000235:genetics; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000235:genetics; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics; D018275:Carcinoma, Lobular / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D018283:Cystadenocarcinoma, Papillary / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D018200:Mixed Tumor, Mullerian / Q000235:genetics; D008969:Molecular Sequence Data; D009378:Neoplasms, Multiple Primary / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D012509:Sarcoma / Q000235:genetics; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases