449 BRCA1 gene mutation carrier analysis in familial breast cancer patients

Abstract

BRCA1, the predisposing gene for familial breast and ovarian cancer localized on chromosome 17q21.3 has been recently cloned. The gene comprises 22 coding exons which span 100 kB of genomic sequence. The protein predicted is 1863 aminoacids long. 31 mutations have been identified in constitutional DNA of affected member from various family of which 22 were distinct. Not one of 22 transcribed exons seems to be a preferential target site for mutations. Overall germline BRCA1 mutations account for 1–2% of all breast cancers and about 3% of ovarian cancers. The lifetime risk of breast and ovarian cancer in BRCA1 mutation carriers is high: the risk of breast cancer is about 50% by age 50 and 70% by age 70. The average risk of ovarian cancer is 40% by age 70. BRCA1 has never been found mutated in sporadic carcinomas, however, loss of heterozigosity in the region of BRCA1 has been observed in 40% of breast and about 60% of ovarian cancers. The lifetime risk to develop the familial form of the disease may be calculated by identifying mutations in BRCA1 or BRCA2 genes. From the screening of 1100 medical records of patients subjected to mastectomy in S. Chiara Hospital in Pisa during the period 1990–1994, the patients with a referred familial recurrence of breast or ovarian cancer were selected for interview. 81 patients belonging to 75 families fitted the BRCA1 eligibility criteria. 37 patients belonging to different families were analyzed for BRCA1 germline mutation. All 37 families are Caucasian and principally reside in Tuscany. Mutation screening was done by ASO (allelic specific oligo hybridization) for three common mutations and by direct sequencing of each of the coding exons. The analysis is under way and approximately 50% ofthe coding region has been screened up to now. We have so far identified 7 mutations of which 5 are different. Three are frameshift and 2 missense. Only one of the mutations found has been reported previously (5382insC). The insertion of an A has been reported in three different families, the aplotype analysis has been performed to ascertain if a common ancestor exist for those three families. No evident correlation between phenotype and genotype has been detected. CG and GC are fellows of the Italian Association for Cancer Research. This work was supported by AIRC and CNR PF ACRO grants.