Anticipation in hereditary breast cancer

To determine whether familial breast cancer occurs at a younger age in successive generations, we reviewed the clinical records of 435 Ashkenazi women with breast cancer referred to our cancer genetic clinic. Ninety-eight who reported a maternal history of breast cancer were selected for further investigation. All women were genotyped for founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). Mean age at dignosis was 55.35 ± 14.21 years in the maternal generation and 48.17 ± 9.32 years in the daughters (t = -4.144; p <0.001). Seventeen women carried a BRCA1 mutation and 12 the 6174delT mutation in BRCA2. Among carriers of the BRCA1 mutation, mean age at diagnosis in the mothers' generation (44 ± 10.18 years) did not differ from that recorded in the daughters (40.76 ± 76 years). Among BRCA2 mutation carriers and non-carriers, the mean age at diagnosis in the daughters' generation (41.4 ± 7.2 and 50.7 ± 8.8 years, respectively) was younger than in the mothers (61.75 ± 14.1 and 57.08 ± 13.7 years, respectively) (t = -4.29; p <0.001 for BRCA2 carriers and t = -3.76; p <0.001 for non-BRCA1/2 carriers). Daughters who were carriers of BRCA1/2 mutations developed breast cancer at a significantly younger age than non-carriers, whilst in the mothers' generation, carriers of BRCA1 mutations developed breast cancer at a significantly younger age than carriers of BRCA2 mutations and non-carriers. BRCA1 mutations predispose to breast cancer at an early age in both mothers and daughters, whereas mutations in BRCA2 were associated with significantly younger age at diagnosis in the second generation. This observation could be related to gene-environmental interactions causing anticipation in BRCA2 mutation carriers.