Abstract
Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01–17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5–38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.
Highlights
Common deleterious founder mutations, 3450del[4] and A1708E in BRCA1, and 3034del[4] in BRCA2
The number of non-proband women diagnosed with breast cancer was too small to estimate the penetrance of BRCA2 mutations, and separate BRCA1 mutations (n = 7 for 3450del[4] and n = 3 for A1708E). This is the largest study on the prevalence of BRCA1/2 mutations in breast/ovarian cancer families and unselected breast cancer patients from Colombia
It is the first report on the prevalence of large-genomic rearrangements (LGRs) in BRCA1/2, and on the cancer risk conferred by specific Colombian BRCA1/2 founder mutations
Summary
Common deleterious founder mutations, 3450del[4] and A1708E in BRCA1, and 3034del[4] in BRCA2 (BIC nomenclature (https://research.nhgri.nih.gov/bic/)[11]. The overall prevalence of BRCA1/2 mutations was 50% in multiple case breast cancer families and 33% in breast and ovarian cancer families. Two studies of unselected breast (and ovarian) cancer patients reported BRCA1/2 mutation frequencies of 1.2% and 15%, respectively[12, 13]. In these studies, the two Colombian BRCA1 founder mutations accounted for 100% (breast cancer patients) and 92% (ovarian cancer patients) of all BRCA1 mutations. The lack of data on possible large-genomic rearrangements (LGRs) in BRCA1/2, and the scarcity of data on the prevalence of BRCA1/2 mutations in Colombian familial and unselected breast cancer patients motivated the present study. We comprehensively screened 68 breast/ovarian cancer families for small-range mutations, 221 families for LGRs, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. We conducted survival analyses to estimate the risk of cancer among relatives of carriers of BRCA1/2 mutations, and the penetrance of specific Colombian BRCA1/2 founder mutations
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