Germline mutations both in BRCA1 and BRCA2 in breast/ovarian cancer families.

A31

Mutations in BRCA1 and BRCA2 gene, two major cancer susceptibility genes, predispose to early onset breast and ovarian cancer. Here we report three Italian non-Ashkenazi families, two with hereditary breast cancer (HBC) and one with hereditary breast/ovarian cancer (BOC), where two independent mutations of both BRCA1 and BRCA2 were found. The prior probability of finding any non-Ashkenazi person or family with mutations in both genes is very low, ranging from 1/250.000 to 1/700.000, thus explaining the scarcity of literature reports among non-Ashkenazi families. Methods and Results: After a genetic counseling genomic DNA was isolated from peripheral blood lymphocytes, the complete BRCA1 and BRCA2 coding region and the splice junctions were analyzed by DHPLC and direct sequencing. Case 1: a BRCA1 mutation of unknown pathogenetic significance; a pathogenic BRCA2. Case 2 and Case 3: a pathogenetic BRCA1; a BRCA2 mutation of unknown pathogenetic significance. In probands 2 and 3 the histopathological characteristics of the neoplasms were typical of the BRCA1 pathogenetic mutation phenotype: early-onset, bilaterality, absence of estrogen and progesterone receptor expression, poor differentiation and high proliferation rate. As compared with carriers of single mutations, the presence of double mutations does not seem to influence negatively the biological and clinical appearance of the disease. This may be attributed to the current lack of knowledge on the role of some mutations. However also in those subjects who are double heterozygotes for known pathogenetic mutations the phenotypic effects of the two mutations do not appear to be cumulative. In family 1 and 3 the pedigree does not suggest an increased genetic susceptibility to cancer. In family 2 one early-onset cancer in a first-degree relative was observed: one of two sisters was diagnosed with pancreatic cancer at age 39. The early-onset of her pancreatic cancer suggests a genetic predisposition rather than a phenocopy. It is unlikely that pancreatic cancer in this family is linked with the BRCA1 mutation rather than a BRCA2 mutation as germinal mutations in the BRCA2 gene are associated with pancreatic cancer much more frequently than BRCA1 mutations. Also, one of the mutations identified in case 1 (4075delGT) has been found in family with more than two cases of pancreatic cancer. Conclusions: Selected families will benefit from testing for both the BRCA1 and BRCA2 genes since the identification of two mutations in a single individual will improve genetic counseling and will increase our understanding of the interaction between the BRCA1 and BRCA2 genes.