127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level.

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BACKGROUND: In most Western populations, 5 -10% of all breast cancer cases can be attributed to major genetic factors such as predisposing mutations in BRCA1 and BRCA2, with early-onset cases generally considered as an indicator of genetic susceptibility. Specific BRCA1 and BRCA2 mutations or different mutation frequencies have been identified in specific populations and ethnic groups. Previous studies in Greek breast and/or ovarian cancer patients with family history have shown that four specific BRCA1 mutations, c.5266dupC, G1738R, and two large genomic rearrangements involving deletions of exons 20 and 24, have a prominent function in the population's BRCA1 and BRCA2 mutation spectrum. METHODS: To estimate the frequency of the above mutations in unselected Greek breast cancer women, we screened 987 unselected cases independently of their family history, collected from major Greek hospitals. RESULTS: Of the 987 patients, 26 (2.6%) were found to carry one of the above mutations in the BRCA1 gene: 13 carried the c.5266dupC mutation (1.3%), 6 carried the exon 24 deletion (0.6%), 3 carried the exon 20 deletion (0.3%), and 4 carried the G1738R mutation (0.4%). Among 140 patients with early-onset breast cancer (o40 years), 14 carried one of the four mutations (10.0%). CONCLUSION: These results suggest that a low-cost genetic screening for only the four prominent BRCA1 mutations may be advisable to all early-onset breast cancer patients of Greek origin.

Hereditary breast and ovarian cancer syndromes can be caused by loss-of-function germline mutations in one of the tumour suppressor genes BRCA1 and BRCA2. In order to characterize these mutations in the Greek population we have been collecting samples from breast/ovarian cancer patients with a family history in collaboration with a large number of Greek Hospitals. Our DNA bank contains samples from more than 300 patients, corresponding to approximately 250 families. In terms of family history this group consists of three subgroups: (i) very early onset (<30 yrs) without family history (10%); (ii) moderate family history (2 members affected, < 50 yrs) (40 %) (iii) strong family history (3'7 members affected) (50 %). Screening of BRCA1 and BRCA2 genes in 150 patients has revealed deleterious mutations in 39 unrelated patients. 5382insC has been found in 11 unrelated families. In summary, the mutation spectrum of BRCA1 and BRCA2 genes in the Greek population seems to be composed by an elevated frequency of 5382insC with the rest being novel or recurrent mutations with low frequency in both genes. Screening of BRCA1 gene is also in progress in collaboration with the Institute of Oncology and Radiology of Serbia. DNA samples have been collected from 32 Serbian families with a family history of breast ovarian cancer. Direct sequencing in exons 2, 5 and 20 of all these samples revealed only one deleterious mutation (C61G) in exon 5 of BRCA1 gene. Screening of the remaining exons is in progress.

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