Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers

Germline alterations of BRCA1 result in susceptibility to breast andovarian cancer. The protein encoded by BRCA1 interacts in vivo with theBRCA1-associated RING domain (BARD1) protein. Accordingly, BARD1 is likelyto be a critical factor in BRCA1-mediated tumor suppression and may alsoserve as a target for tumorigenic lesions in some human cancers. We havenow determined the genomic structure of BARD1 and performed a mutationalanalysis of 58 ovarian tumors, 50 breast tumors and 60 uterine tumors.Seven polymorphisms were detected within the 2.34 kb coding sequence ofBARD1 . Somatically acquired missense mutations were observed in one breastcarcinoma and one endometrial tumor; in at least one of these cases, tumorformation was accompanied by loss of the wild-type BARD1 allele, followingthe paradigm for known tumor suppressor genes. In addition, a germlinealteration of BARD1 was identified in a clear cell ovarian tumor(Gln564His); again, loss of the wild-type BARD1 allele was observed in themalignant cells of this patient. The Gln564His patient was also diagnosedwith two other primary cancers: a synchronous lobular breast carcinoma anda stage IA clear cell endometrioid cancer confined to an endometrial polyp6 years earlier. These findings suggest an occasional role for BARD1mutations in the development of sporadic and hereditary tumors.