Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian breast cancer patients through a hospital-based screening.

Background: Factors predictive of carrying BRCA1 and BRCA2 germline mutations in patients with breast cancer are widely awaited. Genetically-homogeneous Sardinian population could be useful to further define the role of such genetic alterations through a evaluation clinic program. Methods: One hundred and two (15.5%) of 659 consecutively-collected breast cancer patients had a family history of breast cancer and were screened for BRCA1/2 mutations by denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. Results: Three deleterious germline BRCA1/2 mutations were detected in 15 (14.7%) of 102 families; 13 (86.7%) had BRCA2 mutations and two (13.3%) had BRCA1 mutations. A single variant, BRCA2-8765delAG, was the most recurrent mutation in our series: 12 (11.8%) of 102 families and 18 (2.7%) of 657 patients. The average age at diagnosis was significantly younger in families with BRCA1/2 mutations (48.6 years) than in those with no detectable mutation (52.9 years) (P=0.039). Moreover, BRCA1/2 mutations were found at significantly higher rate in families with at least one case of ovarian or male breast cancer (5/12;41.7%) than in those without such an association (10/90;11.1%) (P=0.003). Conclusions: BRCA2 mutations were about six times more prevalent than BRCA1 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, male breast cancer, and three affected generations were all significantly associated to BRCA1/2 mutations. Although our findings further support the hypothesis that additional breast cancer susceptibility genes remain to be identified, such indicators of the presence of BRCA1/2 mutations will be useful in counseling patients about undergoing genetic testing.