{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T21:49:37Z","timestamp":1780523377341,"version":"3.54.1"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Recent 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>WGS 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Carcinoembryonic Antigen-related Cell Adhesion Molecule 24<\/jats:italic>(<jats:italic>CEACAM24<\/jats:italic>) c.247dupG;p.(Val83Glyfs<jats:sup>\u2217<\/jats:sup>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 (<jats:italic>p-<\/jats:italic>value 1.52 \u00d7 10<jats:sup>\u20138<\/jats:sup>) and non-Golden Retriever American Kennel Club breeds (<jats:italic>p-<\/jats:italic>value 2.48 \u00d7 10<jats:sup>\u20135<\/jats:sup>). With no direct ortholog of<jats:italic>CEACAM24<\/jats:italic>in humans but high homology to all CEACAM gene family proteins, all human<jats:italic>CEACAM<\/jats:italic>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<jats:italic>CEACAM6<\/jats:italic>,<jats:italic>CEACAM7<\/jats:italic>, and<jats:italic>CEACAM8<\/jats:italic>are associated with European American breast cancer risk, and rare PTVs in<jats:italic>CEACAM7<\/jats:italic>are associated with breast cancer risk in African Americans. Ultimately, rare PTVs in the entire<jats:italic>CEACAM<\/jats:italic>gene family are associated with breast cancer risk in both European and African Americans with respective<jats:italic>p-<\/jats:italic>values of 1.75 \u00d7 10<jats:sup>\u201313<\/jats:sup>and 1.87 \u00d7 10<jats:sup>\u201304<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study reports the first association of inherited<jats:italic>CEACAM<\/jats:italic>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<jats:italic>CEACAM<\/jats:italic>gene family plays in tumor development, progression, and metastasis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2021.702889","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T08:09:06Z","timestamp":1628582946000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["CEACAM Gene Family Mutations Associated With Inherited Breast Cancer Risk \u2013 A Comparative Oncology Approach to Discovery"],"prefix":"10.3389","volume":"12","author":[{"given":"Anna L. 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