LOW INCIDENCE OF BRCA1 MUTATIONS AMONG ITALIAN FAMILIES WITH BREAST AND OVARIAN-CANCER

Most familial breast or ovarian cancers ave thought to be due to highl y penetrant mutations in the predisposing genes BRCA1 and BRCA2. The c loning of these genes has opened a new era for the genetic counseling of women with a family history of breast or ovarian cancer. To estimat e the incidence of detectable BRCA1 mutations and to define the eligib ility criteria for genetic testing in the Italian population, a total of 53 patients belonging to 46 families clustering multiple cases of b reast and/or ovarian cancer were investigated. Seven families presente d with ovarian cancer only, 16 had both ovarian and breast cancers, an d 23 were characterized by breast cancer only. Using a combination of protein truncation test (PTT) and single strand conformational polymor phism (SSCP) analysis followed, when necessary, by direct sequencing, we found 8 distinct mutations, 2 of these not reported before. Five fr ameshift and 2 nonsense mutations led to a truncated protein. One muta tion was a missense substitution involving a cysteine in the zinc fing er domain. One variant creating an ETS binding site in intron I was fo und but its role was not defined. The percentage of families carrying mutations was 17%. Among the families characterized by ovarian cancer only and by breast and ovarian cancer, the percentage of BRCA1 mutatio ns was 57% and 12.5%, respectively. In contrast, the percentage of alt ered BRCA1 in families with only breast cancers was 9%. In the 46 Ital ian families studied, BRCA1 mutations were detected in fewer kindreds than those previously hypothesized based on linkage analysis, especial ly when these were characterized by breast cancers only. Our results i ndicate that families with a low number of cancer patients should be r eferred for BRCA1 genetic testing mainly when ovarian cancer is presen t. (C) 1998 Wiley-Liss, Inc.