Abstract
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 BRCAl 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 BRCAl and BRCA2 to women with early onset breast cancer.
Highlights
7% of breast cancer arises from inherited genetic mutations [1], the majority of which are in BRCA1 and BRCA2 [2,3,4]
85 of 440 women (19%) with breast cancer diagnosed before age 45 had deleterious mutations, of which 50 occurred in BRCAl and 35 in BRCA2
When results were analyzed by the age of diagnosis of the first degree relative, mutations were significantly more prevalent in women whose first degree family history included breast cancer before age 50 (56 of 185, 30%) than women whose first degree family history was limited to breast cancer diagnosed at or over age 50 (17 of 91, 19%) (P = .042)
Summary
7% of breast cancer arises from inherited genetic mutations [1], the majority of which are in BRCA1 and BRCA2 [2,3,4]. Inherited mutations in these genes are associated with an elevated risk of breast cancer of 56% to 87% by age 70 [5,6], and 33% to 50% before age 50 [6,7]. The risk of ovarian cancer by age 70 is 22% [8] to 44% [5,7] in carriers of BRCA1 mutations, and 27% for carriers of mutations in BRCA2 [9]. It has been shown that a personal or family history of both ovarian and early-onset breast cancer indicates an increased likelihood of an inherited mutation in BRCA1 and BRCA2 [13–
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