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

Abstract

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.

TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells

“…We unexpectedly observed that some genes of the CEACAM family, markers of cancer progression in many solid malignancies [14], were downregulated in MCF-7pR cells (Figure 2a). Our findings seem to corroborate previous results in which CEACAM loss of heterozygosity (LOH) or truncating mutations were associated with tumorigenesis and metastasis in breast cancer [15,16], although this hypothesis needs further study. We also found that pro-apoptotic genes, such as CASP3 and PYCARD, are downregulated in MCF-7pR, whereas the pro-survival BCL2 gene is strongly upregulated (Log2FC = 3.1, padj = 1.15 × 10 −169 ; Figure 2a,b), suggesting an imbalance of cell death/survival stimuli in favor of the latter.…”

An investigation into the role of inherited CEACAM gene family variants and colorectal cancer risk

“…Upon surveying the CEACAM gene family for rare PTVs and missense variants in CRC cases from TCGA and controls from the EVS, no gene-based or gene family-based associations with inherited risk of CRC were revealed. These results were unexpected due to the previous association of rare PTVs in the CEACAM gene family with inherited breast cancer risk [ 16 ], the known similarities between breast cancer and CRC risk [ 1 , 17 , 18 ], and the dis-regulation of CEACAM genes in CRC tumors [ 6 , 8 – 15 ]. Moreover, it has been demonstrated that CEACAM gene function can be affected by even minor genetic changes [ 27 ], and specific residues within CEACAM proteins are crucial for normal function [ 12 , 30 , 31 ].…”

“…Despite the lack of association from aggregation analyses, individual variants were associated with CRC inherited risk (Tables 1 and 2 ). All associations involved individual missense variants; none involved PTVs, unlike the association of CEACAM PTVs with breast cancer risk [ 16 ]. Only four different PTVs were detected amongst all CRC cases, none of which overlapped between ethnicities.…”

“…Recently, rare protein-truncating variants (PTVs) in the CEACAM gene family were associated with the inherited risk of breast cancer [ 16 ]. That discovery, along with aberrant expression of CEACAM genes in CRC tumors and that CRC and breast cancer share many risk factors, including genetics [ 1 , 17 , 18 ], inspired our team to determine if CEACAM mutations are associated with CRC inherited risk.…”

Investigation on the clinicopathological characteristics and BRCA1/2 gene variation of patients in breast cancer pedigrees in Northern Henan Province

“…It has been reported that breast cancer is becoming one of the malignant diseases with high incidence in the world, accounting for about 12% in all kinds of female cancers [1] , and data demonstrated that 5-10% of breast cancer is hereditary because of genetic susceptibility [2,3] . up to now, the genes found susceptible to breast cancer account for 25-30% in hereditary breast cancers [4] ; interestingly, a large number of patients with breast cancer family history do not carry risk variations in these genes, indicating that there may be other genetic risk factors [5] .…”