BRCA1 and BRCA2 founder mutations in patients with bilateral breast cancer

Bilateral breast cancer is traditionally considered an indirect indicator o f inherited predisposition to cancer. To appreciate the contribution of gen etic determinants to bilateral breast cancer in Jewish women we genotyped 5 9 such women for the three predominant mutations in BRCA1 (185delAG and 538 2insC) and BRCA2 (6174delT) that account for the overwhelming majority of B RCA mutations in high-risk Jewish families. Among women with bilateral brea st cancer, 17 mutation carriers (17/55; 29.6%) were identified, Individual mutation frequencies were 18.5% (10/55) for 185delAG, 3.7% (2/55) for 5382i nsC and 7.4% (5/55) for 6174delT. Carrier rate was significantly higher (P < 0.0016) in women with bilateral breast cancer whose first tumour was diag nosed at or before 42 years of age (82%; 14/17) than in women diagnosed aft er 42 years of age (7.9%; 3/38), Among patients with bilateral breast cance r and positive family history 45% (14/31) carried a BRCA mutation. Of these 86% (12/14) had one breast cancer diagnosed at or before 42 years of age. Our results suggest that bilateral breast cancer per se, in most cases, doe s not reflect genetic predisposition, unless associated with early age of o nset (first tumour diagnosed at or before 42 years of age). Although the re lationship between young age and carrier slate in women with bilateral brea st cancer is strong, no significant association between family history and carrier state was found. We can thus speculate that women with early onset breast cancer who carry a BRCA1 or BRCA2 mutation are prone to acquire a se cond breast tumour.