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Genetic testing for BRCA1 and BRCA2 mutations in women with hereditary predisposition to breast and ovarian cancer in Croatia

Among women, breast cancer is the most commonly diagnosed cancer after non-melanoma skin cancer, and it is the leading cause of cancer deaths in Croatia. Ovarian cancer is in the fifth place, both in incidence and mortality. Epidemiological data indicates that 5-15% of breast cancer and 10% of ovarian cancer cases are hereditary, and germline mutations in the tumor suppressor genes Breast Cancer Gene 1 (BRCA1) and Breast Cancer Gene 2 (BRCA2) account for the majority of hereditary breast and ovarian cancers. BRCA1 and BRCA2 are involved in a variety of cellular processes, including maintenance of genome stability, DNA repair via homologous recombination, transcriptional regulation, cell cycle control, chromatin remodeling and ubiquitinylation. Mutations are scattered throughout both genes and include disease-causing mutations as well as unclassified variants. The contribution of BRCA1 and BRCA2 mutations to hereditary breast and ovarian cancer in Croatia is unknown. The purpose of this study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1 and BRCA2 genes in high risk women in Croatia. The screening was performed with high resolution melting analysis, direct sequencing and semi-quantitative multiplex PCR method (Cvok et al. Clin Chem Lab Med 2008 ; 46(10):1376-83). Protocols were certified by EMQN (European Molecular Genetics Quality Network). The complete coding sequences and exon-intron boundaries analyses of both genes were carried out on 160 women with family history of breast and ovarian cancer. Up to now 13 pathogenic mutations were detected, eight in BRCA1, with one previously unpublished, and five in BRCA2 (three previously unpublished). 22 BRCA1 and 36 BRCA2 unclassified variants and polymorphisms were also identified, of which two in BRCA1 and eight in BRCA2 were not previously published. This is the first molecular investigation of the hereditary predisposition to breast and ovarian cancer in BRCA1 and BRCA2 genes in Croatia. Samples were collected from different regions of the country and the level of pathogenic mutations and distribution of polymorphic variants will contribute to population statistics for 4.5 million population of Croatia. This study was funded by The Terry Fox Run 2009 donation and supported by The Terry Fox Foundation and Croatian League Against Cancer.

Cancer Genetics; Cancer Syndromes; Genetic Testing; Population Genetics; Risk Assessment; SNP Analysis/Discovery

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