AUTHOR=Huskey Anna L. W. , McNeely Isaac , Merner Nancy D. 

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

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.702889

DOI=10.3389/fgene.2021.702889

ISSN=1664-8021

ABSTRACT=<sec><title>Introduction</title><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.</p></sec><sec><title>Methods</title><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.</p></sec><sec><title>Results</title><p><italic>Carcinoembryonic Antigen-related Cell Adhesion Molecule 24</italic> (<italic>CEACAM24</italic>) c.247dupG;p.(Val83Glyfs<sup>∗</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 (<italic>p-</italic>value 1.52 × 10<sup>–8</sup>) and non-Golden Retriever American Kennel Club breeds (<italic>p-</italic>value 2.48 × 10<sup>–5</sup>). With no direct ortholog of <italic>CEACAM24</italic> in humans but high homology to all CEACAM gene family proteins, all human <italic>CEACAM</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 <italic>CEACAM6</italic>, <italic>CEACAM7</italic>, and <italic>CEACAM8</italic> are associated with European American breast cancer risk, and rare PTVs in <italic>CEACAM7</italic> are associated with breast cancer risk in African Americans. Ultimately, rare PTVs in the entire <italic>CEACAM</italic> gene family are associated with breast cancer risk in both European and African Americans with respective <italic>p-</italic>values of 1.75 × 10<sup>–13</sup> and 1.87 × 10<sup>–04</sup>.</p></sec><sec><title>Conclusion</title><p>This study reports the first association of inherited <italic>CEACAM</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 <italic>CEACAM</italic> gene family plays in tumor development, progression, and metastasis.</p></sec>