Hereditary Susceptibility to Breast Cancer: Significance of Age of Onset in Family History and Contribution of BRCA1 and BRCA2

OBJECTIVE To correlate mutations in BRCA1 and BRCA2 with family history of breast cancer in a first-degree relative for women diagnosed with breast cancer before age 45 who do not have a personal or family history of ovarian cancer. METHODS Family history for women with breast cancer diagnosed before age 45 was provided by ordering physicians via a test requisition form designed for this purpose. Gene analysis was performed by dye primer sequencing for the entire coding regions of BRCA1 and BRCA2. Because a personal and family history of ovarian cancer are known to be significantly associated with mutations, women with either were excluded from analysis. RESULTS Overall, deleterious mutations in BRCA1 or BRCA2 were identified in 85 of 440 women (19%) with breast cancer under 45. Mutations were identified in 73 of 276 women (26%) with a first degree family history of breast cancer compared to 12 of 164 without (7%) (P < .0001). When results were analyzed by the age of diagnosis in first degree relatives, mutations were identified in 56 of 185 women (30%) with at least one first degree relative with breast cancer diagnosed before age 50 compared with 17 of 91 women (19%), where the first degree family history of breast cancer was at or over age 50 (P = .042). CONCLUSION Among women with breast cancer diagnosed before age 45, a first-degree relative diagnosed with the disease under age 50 is an indicator of a mutation in BRCA1 or BRCA2 even in the absence of a family history of ovarian cancer. Therefore, women diagnosed with early-onset breast cancer should be asked about the age of onset in any first-degree relative diagnosed with the disease, as well as about any family history of ovarian cancer. Mutations in BRCA2 account for a substantial proportion of hereditary breast cancer. Therefore, studies that are limited to BRCA1 or that do not analyze by age of onset of breast cancer in relatives may underestimate the contribution of mutations in BRCA1 and BRCA2 to women with early onset breast cancer.