New Insights Into c.815_824dup Pathogenic Variant of BRCA1 in Inherited Breast Cancer: A Founder Mutation of West African Origin

Founder mutations have been reported in BRCA1 and BCRA2 in different ethnic groups with inherited breast cancer. Testing of targeted mutations in specific populations is important for cancer prevention in mutation carriers. In Sub-Saharan Africa, only a few studies have reported specific founder mutations in inherited breast cancer. The pathogenic variant c.815_824dup of BRCA1 has been reported as the most frequent among African American populations with inherited breast cancer and was supposed to have a West African origin. Recent report from Senegal identified this variant in women with inherited breast cancer at the highest frequency ever reported. The variant was linked to a common haplotype confirming its founder effect in West Africa. In this article, we review the mutation history of c.815_824dup and discuss how it spread out of Africa through the transatlantic slave trade.

CEACAM Gene Family Mutations Associated With Inherited Breast Cancer Risk – A Comparative Oncology Approach to Discovery

IntroductionRecent studies comparing canine mammary tumors (CMTs) and human breast cancers have revealed remarkable tumor similarities, identifying shared expression profiles and acquired mutations. CMTs can also provide a model of inherited breast cancer susceptibility in humans; thus, we investigated breed-specific whole genome sequencing (WGS) data in search for novel CMT risk factors that could subsequently explain inherited breast cancer risk in humans.MethodsWGS was carried out on five CMT-affected Gold Retrievers from a large pedigree of 18 CMT-affected dogs. Protein truncating variants (PTVs) detected in all five samples (within human orthlogs) were validated and then genotyped in the 13 remaining CMT-affected Golden Retrievers. Allele frequencies were compared to canine controls. Subsequently, human blood-derived exomes from The Cancer Genome Atlas breast cancer cases were analyzed and allele frequencies were compared to Exome Variant Server ethnic-matched controls.ResultsCarcinoembryonic Antigen-related Cell Adhesion Molecule 24 (CEACAM24) c.247dupG;p.(Val83Glyfs∗48) was the only validated variant and had a frequency of 66.7% amongst the 18 Golden Retrievers with CMT. This was significant compared to the European Variation Archive (p-value 1.52 × 10–8) and non-Golden Retriever American Kennel Club breeds (p-value 2.48 × 10–5). With no direct ortholog of CEACAM24 in humans but high homology to all CEACAM gene family proteins, all human CEACAM genes were investigated for PTVs. A total of six and sixteen rare PTVs were identified in African and European American breast cancer cases, respectively. Single variant assessment revealed five PTVs associated with breast cancer risk. Gene-based aggregation analyses revealed that rare PTVs in CEACAM6, CEACAM7, and CEACAM8 are associated with European American breast cancer risk, and rare PTVs in CEACAM7 are associated with breast cancer risk in African Americans. Ultimately, rare PTVs in the entire CEACAM gene family are associated with breast cancer risk in both European and African Americans with respective p-values of 1.75 × 10–13 and 1.87 × 10–04.ConclusionThis study reports the first association of inherited CEACAM mutations and breast cancer risk, and potentially implicates the whole gene family in genetic risk. Precisely how these mutations contribute to breast cancer needs to be determined; especially considering our current knowledge on the role that the CEACAM gene family plays in tumor development, progression, and metastasis.

Cancer risk management and family communication of genetic test results among women with inherited breast cancer genes.

1532 Background: Identification of inherited breast cancer may guide care, with benefits amplified through family testing. Methods: Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about cancer risk management, family communication of genetic test results, and family testing. Comparisons were made across genes. Results: The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and 61% had a prior breast cancer diagnosis. For women with P/LP variants in BRCA1/2, PALB2, and ATM/CHEK2, bilateral mastectomy rates were 79%, 61%, and 52%, respectively; and risk-reducing oophorectomy rates were 89%, 30%, and 37%, respectively. All women with PALB2 and ATM/CHEK2 P/LP variants with a bilateral mastectomy had a personal or family history of breast cancer; however, only 27% of those with a risk-reducing oophorectomy had a family history of ovarian cancer. Family communication of genetic test results and family testing rates were higher for those with P/LP variants in BRCA1/2 compared to others. Conclusions: Bilateral mastectomy and risk-reducing oophorectomy were relatively common among women with PALB2 and ATM/CHEK2 P/LP variants in our study, suggesting overtreatment through risk-reducing surgery. Furthermore, strategies to improve family communication of genetic test results and family testing are needed to amplify testing benefits.