AIM: The aim of this study was to further delineate the extent and nature of mutations in the BRCA1 and BRCA2 genes, responsible for hereditary breast and ovarian cancer in Greek families.

MATERAILS & METHODS: Genomic DNA was isolated from whole peripheral blood of patients referred to our center for mutation analysis of the BRCA1 and BRCA2 genes. Patients were included on the basis of affected family members, types of cancer present in the family and age at diagnosis of breast cancer in the proband. Families were subdivided into high, medium and low risk depending on the number of affected family members, types of cancer diagnosed in the family and age at diagnosis of affected family members. In total, 675 families have been analyzed by our group in the past 4 years. Mutation analysis in all cases included sequencing of the coding region and the splice sites of the two genes. In addition, MLPA analysis was carried in 585 of the patients.

RESULTS: In total, a pathogenic mutation has been identified in 12% of the 675 patients analyzed. Of the 78 mutations identified in total, 13 (17%) were large genomic rearrangements. These were deletions of exons 8, 20, 23, 23-24 and the entire BRCA1 gene, in addition to a duplication of exons 3-8 of the BRCA1 gene. As far as BRCA2 is involved deletions of exons 3, 15 and the entire BRCA2 gene were detected. All deletions were confirmed by use of other MLPA probe sets and/or relative quantitation by Real Time PCR. Of the rearrangements identified, two, namely deletions of exon 20 and exons 23-24 of the BRCA1 gene were identified in more than one unrelated families. In addition, the recurrent mutations 5382insC and G1738R, which have been previously identified as founder mutations in the Greek population, were identified in multiple unrelated analyzed families.

CONCLUSIONS: Our results indicate that different large genomic rearrangements account for an important proportion (17%) of the mutations in the BRCA1 and BRCA2 genes, in Greek families at risk of carrying a germline mutation as judged by family / personal history. The use of the available technologies for the identification of such mutational events is therefore necessary when carrying out complete analysis of the genes in high risk families of Greek background.

Citation Format: Angela Apessos, Eirini Papadopoulou, Vassiliki Metaxa-Mariatou, Konstantinos Agiannitopoulos, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Maria Vasilaki-Antonatou, Antonios Keramopoulos, Nikolaos Bredakis, Aristeidis Tsiftsoglou, Georgios Kesisis, Stylianos Kakolyris, Nikolaos Touroutoglou, Ioannis Natsiopoulos, Konstantinos Papazisis, Georgios Nasioulas. Different genomic rearrangements account for 17% of BRCA1/2 mutations in Greece [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-08.