Germline mutations of BRCA1-associated RING domain (BARD1) gene in breast and/or ovarian families negative for BRCA1 and 2 alterations

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BARD1 (BRCA1-associated RING domain) has been identified by yeast two-hybrid screening as a protein specifically interacting with the product of BRCA1 gene. Somatic and germline mutations of BARD1 have been detected in sporadic breast, ovarian and endometrial cancers. In this study, we evaluate the frequency of BARD1 germline mutations in 20 Italian hereditary breast and breast-ovarian families tested negative for BRCA1 and BRCA2 mutations. Two families were breast-ovarian, 11 had more than four cases of breast cancer and five had only two affected in the family. Mutational analysis was performed by SSCP for the entire coding region and exon-intron splice boundaries of BARD1 gene. Direct sequence analysis was used to identify the genetic alterations. We found three different germline alterations of the BARD1 gene, two missense and one frameshift: a G>C transversion in codon 557 that produces an aminoacidic change Cys>Ser in exon 7; a A>G transition in codon 295 that produces an aminoacidic change Asn>Ser in exon 4; a 21bp deletion after nucleotide 1071 that produces an in-frame deletion of 7 aminoacid in exon 4.

A group of 20 sporadic breast cancers below 40 years of age, selected as a control group was analyzed. We found only a somatic mutation in one tumor.

The mutation was the same in-frame deletion found in the family group. A study of loss of heterozigosity of BARD1 locus (D2S143, D2S164 and D2S295 markers) in the tumor tissues of patients carrying the BARD1 mutations is under investigation.

These data suggest that BARD1 could be involved in the susceptibility of hereditary breast and ovarian tumors.

This work was supported by AIRC.