A Role ofBRCA1andBRCA2germline mutations in breast cancer susceptibility within Sardinian population

Background.In recent years, numerous studies have assessed the prevalence of germline mutations inBRCA1andBRCA2genes in various cohorts. We here extensively investigated the prevalence and geographical distribution ofBRCA1-2mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence ofBRCA1-2germline mutations was also evaluated.Methods.Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened forBRCA1-2mutations by DHPLC analysis and DNA sequencing. Association ofBRCA1andBRCA2mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.Results and Conclusion.Overall, 8BRCA1and 5BRCA2deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found inBRCA2gene. The geographical distribution ofBRCA1-2mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where aBRCA2 c.8764_8765delAGmutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (whereBRCA2mutations are still more common thanBRCA1mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (whereBRCA1mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence ofBRCA1-2germline mutations.