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CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5 (carcinoembryonic antigen))

Written2015-08Naoto Shirasu, Masahide Kuroki
Department of Biochemistry, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan (NS) / shirasu@fukuoka-u.ac.jp; Professor Emeritus, Fukuoka University 5-16-47 Tamura, Sawara-ku, Fukuoka 814-0175, Japan (MK) / kurokima@fukuoka-u.ac.jp

Abstract The CEACAM5 gene encodes carcinoembryonic antigen (CEA), which was first identified as an oncofetal antigen in 1965 in human colon cancer tissue extracts. CEA is a heavily glycosylated protein that belongs to the CEA-related cell adhesion molecule (CEACAM) family of the immunoglobulin (Ig) gene superfamily. CEA is closely related to CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7, and CEACAM8. CEA is also expressed at low levels in normal tissues of epithelial origin in a polarized manner and found only at the luminal portion of the cell, but not at the basolateral surface. CEA in normal tissues is now considered to protect the luminal organs of the body from microbial infection by binding and trapping infectious microorganisms. In contrast, the expression of CEA is frequently high in various carcinomas. Cancer cells not only lose polarized expression of CEA, but also actively cleave CEA from their surface by phospholipases, resulting in increased serum concentrations of CEA. The serum CEA levels may be monitored to detect a response to cancer therapy or disease recurrence and serve as a prognostic indicator in patients with various cancers, where elevated levels indicate a poor prognosis and correlate with a reduced overall survival. Cell-bound CEA has served as a target for tumor imaging and various cancer therapies.

Keywords CEACAM5, CEA, CEA gene family, CD66e, tumor marker

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCEA
carcinoembryonic antigen-related cell adhesion molecule 5
Alias_symbol (synonym)CD66e
Other alias
HGNC (Hugo) CEACAM5
LocusID (NCBI) 1048
Atlas_Id 40047
Location 19q13.2  [Link to chromosome band 19q13]
Location_base_pair Starts at 42212504 and ends at 42234341 bp from pter ( according to hg19-Feb_2009)  [Mapping CEACAM5.png]
Local_order cent ---- CEACAM21 - CEACAMP3 - CEACAM4 - CEACAM7 - CEACAM5 - CEACAM6 - CEACAM3 - CEACAM1 - CEACAMP2 - CEACAM8 - CEACAMP1 - CEACAMP5 ---- qter
 
  A schematic representation of the chromosomal arrangement of the CEACAM family genes. Main members (CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6 CEACAM7 and CEACAM8) of the CEACAM family are localized in the region of the chromosome 19q13.2.
Fusion genes
(updated 2016)
CEACAM5 (19q13.2) / PDE5A (4q26)FYN (6q21) / CEACAM5 (19q13.2)PACSIN2 (22q13.2) / CEACAM5 (19q13.2)
Note The CEACAM5 gene is classified as a member of the CEACAM family (24 genes), which belongs to the CEA gene family (35 genes) together with the pregnancy-specific glycoprotein (PSG) family (11 genes). The CEA gene family is a member of the immunoglobulin (Ig) supergene family (Thompson et al., 1991; Pavlopoulou and Scorilas, 2014).

DNA/RNA

Note Out of 24 CEACAM family genes, twelve members (i.e., CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEACAM16, CEACAM18, CEACAM19, CEACAM20 and CEACAM21) are expressed while the other 12 genes are pseudogenes (Pavlopoulou and Scorilas, 2014). All the CEACAM family genes are localized in the 19q13.2-19q13.4 region. Although the newly given protein names encoded by those active genes are the same as the gene names (Beauchemin et al., 1999), that of CEACAM5 is still CEA because the name of CEA has clinically been widely used for a long time. Splice variants isoforms of CEACAM/CEA have been detected, and the resulting protein isoforms were not only co-expressed with full-length CEA but also co-secreted into the culture medium by gastrointestinal cancer cell lines (Hatakeyama et al., 2013).
 
  (A) Alternative splicing of CEA precursor mRNA leads to the shorter isoforms with different domain structures. Protein-coding exons (exons 1-9) are shown as yellow boxes; the 3'-untranslated exon 10, the light yellow box. (B) Schematic representations of the protein domain structures of the translated CEA transcripts. The black sigmoidal line attached to the B3 IgC-like domain indicates a glycosylphosphatidylinositol (GPI) anchor to the plasma membrane (see below).
Description The CEACAM5 gene, spanning a length of approximately 21 kb, consists of 9 exons with a 3'-non-coding exon (exon 10).
Transcription The primary CEA transcript encodes a protein with an Ig variable region (IgV)-like domain, termed N, followed by six Ig constant region (IgC)-type 2-like domains, termed A1, B1, A2, B2, A3, and B3. In some normal and cancer cells, the transcript is subjected to alternative splicing, resulting in the generation of several CEA isoforms (Hatakeyama et al., 2013). The CEA transcript with skipping of exons 3-4 encodes the variant with a five-domain structure (N-A2-B2-A3-B3 (5D)), while the transcript lacking the sequence from the 3' end of exon 3 to the 5' end of exon 7 relative to the full-length transcript contains only three domains (N-A1-B3 (3D)).
Pseudogene Out of 24 CEACAM family genes, twelve are pseudogenes and have been identified in the CEA family gene cluster (Pavlopoulou and Scorilas, 2014).

Protein

Note The CEACAM5 gene encodes CEA, which is the most widely used tumor marker for the diagnosis and monitoring of various cancers (see below). CEA is composed of 642 amino acids (a molecular mass of approximately 70kDa) and has 28 potential N-linked glycosylation sites (Oikawa et al., 1987; Nicholson and Stanners, 2007). CEA contains 24-26 asparagine-linked sugar chains in one molecule (Yamashita et al., 1987) and its final molecular mass is approximately 180kDa (Thompson et al., 1991).
 
  (A) The gene structure and protein domain model of the CEA molecule. CEA encoded by the CEACAM5 gene is synthesized as a precursor with a signal peptide (S) followed by 668 amino acids of the putative molecule; the first N-terminal domain (N domain) is followed by six IgC-like domains (A1, B1, A2, B2, A3, and B3 domains) and the last C-terminal hydrophobic domain (C domain) (Oikawa et al., 1987). Exons 1 and 9 include a 5'-untranslated region (5'-UTR) and a 3'-untranslated region (3'-UTR), respectively (Schrewe et al., 1990). (B) Schematic representation of the CEA protein structure. CEA is finally anchored to the membrane by the simultaneously occurring proteolysis of the C domain and replacement with the GPI anchor immediately after synthesis (Takami et al., 1988).
Description Among the main CEACAM family members (CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6 CEACAM7 and CEACAM8), the genes encoding proteins with transmembrane domains were assigned the CEACAM consecutive numbers 1-4, and the genes encoding GPI-anchored proteins including CEA were assigned the CEACAM numbers 5-8 (Beauchemin et al., 1999).
Expression Many CEACAM family proteins, such as CEACAM1, CEACAM8, CEACAM6 and CEACAM3, are known to be expressed in hematopoietic cells (Nagel and Grunert, 1995; Baeclay et al., 1997). In contrast, CEA has not been detected in hematopoietic cells and shows a more limited tissue localization in normal tissues including the tongue, esophagus, stomach, duodenum, appendix, colon, trachea (Nap et al., 1988; Kuroki et al., 1981) and lung (Nouwen et al., 1986). The CEA expression in those organs starts during the early fetal period (9-14 weeks) and appears to continue throughout one's lifespan (Nap et al., 1988). Increased expression of CEA has also been observed in various cancers including colorectal carcinoma (Jothy et al., 1993), gastric carcinoma (Kinugasa et al., 1998), pancreatic carcinoma (Shi et al., 1994), gall bladder carcinoma (Shi et al., 1994), lung adenocarcinoma (Robbins et al., 1993), small cell lung carcinoma (Kim et al., 1992), breast carcinoma (Cournoyer et al., 1988), urinary bladder carcinoma (Shi et al., 1994), mucinous ovarian carcinoma (Thompson et al., 1994), serous ovarian carcinoma (Thompson et al., 1993) and endometrial adenocarcinoma (Thompson et al., 1993). It is usually expressed in corresponding metastatic lesions as well, due to its involvement in tumor progression and metastasis.
Localisation CEA is localized to columnar epithelial cells and goblet cells of the colon, mucous neck cells and pyloric mucous cells of the stomach, squamous epithelial cells of the tongue, esophagus and cervix, secretory epithelia and duct cells of sweat glands and epithelial cells of the prostate (Nap et al., 1988; Kodera et al., 1993; Prall et al., 1996). Studies using immunoelectron microscopy using a specific monoclonal antibody for CEA demonstrate that CEA is specifically localized to the apical surface of mature enterocytes (Ahnen et al., 1982; Baranov et al., 1994; Frãngsmyr et al., 1999). No staining is seen at the basolateral surfaces of the enterocytes. The structure that is specifically stained is the apical glycocalyx (= fuzzy coat)/microvillus region of the mature enterocytes. The fuzzy coat is made up of microvesicles and filaments. The microvesicles are formed by the blebbing of microvillus membrane and subsequent pinching off. The finding that CEA in normal colon is released via CEA-coated vesicles agrees with the findings which showed that more than 90% of total CEA in feces exist in a membrane-bound form and that it can be released from the membranes by phosphatidylinositol-specific phospholipase C (Kuroki et al., 1994; Kinugasa et al., 1994).
Function In vitro studies with tumor cell lines have demonstrated that CEA, like other CEA gene family members, can act as homophilic and heterophilic adhesion molecules when expressed on the tumor cell surface (Benchimol et al., 1989; Oikawa et al., 1992; Zhou et al., 1993). Therefore, in the tumor environment it is possible that CEA plays some role as a contact-mediating device when tumor cells are invading new sites. In normal physiology, however, it appears unlikely that CEA is involved in intercellular adhesion due to their apical localization on polarized cells. CEA in normal tissues is now considered to protect the luminal organs of the body from microbial infection by binding and trapping infectious microorganisms. Those organs are the colon and perhaps other areas, such as the upper alimentary tract, the respiratory tract, the urinary bladder, and the skin (sweat glands), where the microbial load is a routine event (Hammarström, 1999).
Homology The CEACAM5 gene homologue is present in primates such as chimpazees, orangutans, macaques and marmosets, but not in rodents such as mice and rats (Pavlopoulou and Scorilas, 2014).

Mutations

Note As of July 2015, the 245 single-nucleotide polymorphisms (SNPs) of the CEACAM gene have been included in the NCBI SNP database (dbSNP), and there are 19 independent SNPs located within the coding region.  However, to date, no clinical significance of these CEACAM SNPs has been described.

Implicated in

Note
  
Entity Various cancers
Note As described above, CEA is widely expressed not only on the surface of tumor cells, but also on normal epithelial cells of the luminal organs of the body. These facts demonstrate that CEA is no longer a carcinoembryonic (oncofetal) antigen, rather it should be considered to be a normal tissue component with retained/increased expression in tumors (Kuroki et al., 1988; Hammarström, 1999). The degree of its expression is related to the state of differentiation of the normal or tumor cell; highly differentiated cells express higher levels of CEA (Hammarström, 1999). The localization of CEA in normal adult tissues is, however, restricted to the apical surface of the epithelial cell membranes facing the lumen, so that CEA is not directly exposed to the tissue fluid or blood flow. In contrast, in tumor tissues that no longer conform to the single-layer organization by invading through the basement membrane in multicellular arrays, CEA is typically localized to all sides of the cell surface, directly facing the blood flow or tissue fluid (Hammarström, 1999; Khare et al., 2001). As the tumor size increases, more CEA will accumulate in the blood. Hence, the serum CEA levels may be monitored to detect a response to anticancer therapy or disease recurrence in various cancers, especially in colorectal cancer (Goldstein Mitchell, 2005; Locker et al., 2006). Immunohistochemical staining of CEA using surgically- or biopsy-removed specimens is also helpful as a diagnostic aid in patients with various cancers (Kuroki et al., 2002).
Prognosis Serum CEA serves as a prognostic indicator in patients with various types of cancer, where elevated levels indicate a poor prognosis and correlate with a reduced overall survival (Duffy, 2001; Locker et al., 2006).
  

To be noted

The clear contrast of the CEA localization pattern between normal tissues and tumor tissues suggests that tumor cell-bound CEA may serve as a potential target for tumor imaging (Hong et al., 2008) and various kinds of cancer therapies using anti-CEA monoclonal antibodies or their genes (Khare et al., 2001; Tanaka et al., 2006; Baek et al., 2011; Peng et al., 2012; Kuroki and Shirasu, 2014; Shirasu et al, 2014).

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Citation

This paper should be referenced as such :
Shirasu N, Kuroki M
CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5 (carcinoembryonic antigen));
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/CEACAM5ID40047ch19q13.html


External links

Nomenclature
HGNC (Hugo)CEACAM5   1817
Cards
AtlasCEACAM5ID40047ch19q13
Entrez_Gene (NCBI)CEACAM5  1048  carcinoembryonic antigen related cell adhesion molecule 5
AliasesCD66e; CEA
GeneCards (Weizmann)CEACAM5
Ensembl hg19 (Hinxton)ENSG00000105388 [Gene_View]  chr19:42212504-42234341 [Contig_View]  CEACAM5 [Vega]
Ensembl hg38 (Hinxton)ENSG00000105388 [Gene_View]  chr19:42212504-42234341 [Contig_View]  CEACAM5 [Vega]
ICGC DataPortalENSG00000105388
TCGA cBioPortalCEACAM5
AceView (NCBI)CEACAM5
Genatlas (Paris)CEACAM5
WikiGenes1048
SOURCE (Princeton)CEACAM5
Genetics Home Reference (NIH)CEACAM5
Genomic and cartography
GoldenPath hg19 (UCSC)CEACAM5  -     chr19:42212504-42234341 +  19q13.1-q13.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)CEACAM5  -     19q13.1-q13.2   [Description]    (hg38-Dec_2013)
EnsemblCEACAM5 - 19q13.1-q13.2 [CytoView hg19]  CEACAM5 - 19q13.1-q13.2 [CytoView hg38]
Mapping of homologs : NCBICEACAM5 [Mapview hg19]  CEACAM5 [Mapview hg38]
OMIM114890   
Gene and transcription
Genbank (Entrez)AB852566 AB852567 AK223101 AK310844 BC034671
RefSeq transcript (Entrez)NM_001291484 NM_001308398 NM_004363
RefSeq genomic (Entrez)NC_000019 NC_018930 NT_011109 NW_004929415
Consensus coding sequences : CCDS (NCBI)CEACAM5
Cluster EST : UnigeneHs.709196 [ NCBI ]
CGAP (NCI)Hs.709196
Alternative Splicing GalleryENSG00000105388
Gene ExpressionCEACAM5 [ NCBI-GEO ]   CEACAM5 [ EBI - ARRAY_EXPRESS ]   CEACAM5 [ SEEK ]   CEACAM5 [ MEM ]
Gene Expression Viewer (FireBrowse)CEACAM5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1048
GTEX Portal (Tissue expression)CEACAM5
Protein : pattern, domain, 3D structure
UniProt/SwissProtP06731   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP06731  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP06731
Splice isoforms : SwissVarP06731
PhosPhoSitePlusP06731
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub    Ig_sub2    Ig_V-set    Immunoglobulin   
Domain families : Pfam (Sanger)I-set (PF07679)    ig (PF00047)    Ig_2 (PF13895)    V-set (PF07686)   
Domain families : Pfam (NCBI)pfam07679    pfam00047    pfam13895    pfam07686   
Domain families : Smart (EMBL)IG (SM00409)  IGc2 (SM00408)  
Conserved Domain (NCBI)CEACAM5
DMDM Disease mutations1048
Blocks (Seattle)CEACAM5
PDB (SRS)1E07    2QSQ    2QST    2VER   
PDB (PDBSum)1E07    2QSQ    2QST    2VER   
PDB (IMB)1E07    2QSQ    2QST    2VER   
PDB (RSDB)1E07    2QSQ    2QST    2VER   
Structural Biology KnowledgeBase1E07    2QSQ    2QST    2VER   
SCOP (Structural Classification of Proteins)1E07    2QSQ    2QST    2VER   
CATH (Classification of proteins structures)1E07    2QSQ    2QST    2VER   
SuperfamilyP06731
Human Protein AtlasENSG00000105388
Peptide AtlasP06731
HPRD00274
IPIIPI00027486   IPI00743702   IPI00880101   
Protein Interaction databases
DIP (DOE-UCLA)P06731
IntAct (EBI)P06731
FunCoupENSG00000105388
BioGRIDCEACAM5
STRING (EMBL)CEACAM5
ZODIACCEACAM5
Ontologies - Pathways
QuickGOP06731
Ontology : AmiGOintegral component of plasma membrane  negative regulation of myotube differentiation  basolateral plasma membrane  anchored component of membrane  homotypic cell-cell adhesion  GPI anchor binding  identical protein binding  protein homodimerization activity  negative regulation of apoptotic process  extracellular exosome  integral component of external side of plasma membrane  negative regulation of anoikis  
Ontology : EGO-EBIintegral component of plasma membrane  negative regulation of myotube differentiation  basolateral plasma membrane  anchored component of membrane  homotypic cell-cell adhesion  GPI anchor binding  identical protein binding  protein homodimerization activity  negative regulation of apoptotic process  extracellular exosome  integral component of external side of plasma membrane  negative regulation of anoikis  
REACTOMEP06731 [protein]
REACTOME Pathways163125 [pathway]   202733 [pathway]   
NDEx NetworkCEACAM5
Atlas of Cancer Signalling NetworkCEACAM5
Wikipedia pathwaysCEACAM5
Orthology - Evolution
OrthoDB1048
GeneTree (enSembl)ENSG00000105388
Phylogenetic Trees/Animal Genes : TreeFamCEACAM5
HOVERGENP06731
HOGENOMP06731
Homologs : HomoloGeneCEACAM5
Homology/Alignments : Family Browser (UCSC)CEACAM5
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCEACAM5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CEACAM5
dbVarCEACAM5
ClinVarCEACAM5
1000_GenomesCEACAM5 
Exome Variant ServerCEACAM5
ExAC (Exome Aggregation Consortium)CEACAM5 (select the gene name)
Genetic variants : HAPMAP1048
Genomic Variants (DGV)CEACAM5 [DGVbeta]
DECIPHER (Syndromes)19:42212504-42234341  ENSG00000105388
CONAN: Copy Number AnalysisCEACAM5 
Mutations
ICGC Data PortalCEACAM5 
TCGA Data PortalCEACAM5 
Broad Tumor PortalCEACAM5
OASIS PortalCEACAM5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCEACAM5  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCEACAM5
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CEACAM5
DgiDB (Drug Gene Interaction Database)CEACAM5
DoCM (Curated mutations)CEACAM5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CEACAM5 (select a term)
intoGenCEACAM5
NCG5 (London)CEACAM5
Cancer3DCEACAM5(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM114890   
Orphanet
MedgenCEACAM5
Genetic Testing Registry CEACAM5
NextProtP06731 [Medical]
TSGene1048
GENETestsCEACAM5
Huge Navigator CEACAM5 [HugePedia]
snp3D : Map Gene to Disease1048
BioCentury BCIQCEACAM5
ClinGenCEACAM5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1048
Chemical/Pharm GKB GenePA26361
Clinical trialCEACAM5
Miscellaneous
canSAR (ICR)CEACAM5 (select the gene name)
Probes
Litterature
PubMed157 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCEACAM5
EVEXCEACAM5
GoPubMedCEACAM5
iHOPCEACAM5
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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