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

2015-08-01 Naoto Shirasu , Masahide Kuroki Affiliation

Identity

HGNC

CEACAM5

LOCATION

19q13.2

IMAGE

LEGEND

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.

LOCUSID

1048

ALIAS

CD66e,CEA

FUSION GENES

Show Gene Fusions

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.

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).

Proteins

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 ones 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

Entity name

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).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
7042066	1982	Ultrastructural localization of carcinoembryonic antigen in normal intestine and colon cancer: abnormal distribution of CEA on the surfaces of colon cancer cells.	Ahnen DJ et al
20924362	2011	Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells.	Baek H et al
8205554	1994	Expression of carcinoembryonic antigen and nonspecific cross-reacting 50-kDa antigen in human normal and cancerous colon mucosa: comparative ultrastructural study with monoclonal antibodies.	Baranov V et al
11501563	1999	Redefined nomenclature for members of the carcinoembryonic antigen family.	Beauchemin N et al
2702691	1989	Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule.	Benchimol S et al
2835154	1988	Transcription of genes of the carcinoembryonic antigen family in malignant and nonmalignant human tissues.	Cournoyer D et al
11274010	2001	Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful?	Duffy MJ et al
10436421	1999	Four carcinoembryonic antigen subfamily members, CEA, NCA, BGP and CGM2, selectively expressed in the normal human colonic epithelium, are integral components of the fuzzy coat.	Frängsmyr L et al
16100946	2005	Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer.	Goldstein MJ et al
10202129	1999	The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues.	Hammarström S et al
24070190	2013	Novel protein isoforms of carcinoembryonic antigen are secreted from pancreatic, gastric and colorectal cancer cells.	Hatakeyama K et al
19578524	2008	Radionuclide-Based Cancer Imaging Targeting the Carcinoembryonic Antigen.	Hong H et al
11196189	2001	Specifically targeted killing of carcinoembryonic antigen (CEA)-expressing cells by a retroviral vector displaying single-chain variable fragmented antibody to CEA and carrying the gene for inducible nitric oxide synthase.	Khare PD et al
1330929	1992	Expression of carcinoembryonic antigen and related genes in lung and gastrointestinal cancers.	Kim J et al
9533775	1998	Expression of four CEA family antigens (CEA, NCA, BGP and CGM2) in normal and cancerous gastric epithelial cells: up-regulation of BGP and CGM2 in carcinomas.	Kinugasa T et al
8318403	1993	Expression of carcinoembryonic antigen (CEA) and nonspecific crossreacting antigen (NCA) in gastrointestinal cancer; the correlation with degree of differentiation.	Kodera Y et al
3203325	1988	Active production and membrane anchoring of carcinoembryonic antigen observed in normal colon mucosa.	Kuroki M et al
6160910	1981	Purification and characterization of carcinoembryonic antigen-related antigens in normal adult feces.	Kuroki M et al
8190712	1994	Fractionation of carcinoembryonic antigen and related antigens in normal adult feces using a gradient medium Percoll.	Kuroki M et al
25075090	2014	Novel treatment strategies for cancer and their tumor-targeting approaches using antibodies against tumor-associated antigens.	Kuroki M et al
12553066	2002	Significance of tumor-associated antigens in the diagnosis and therapy of cancer: an overview.	Kuroki M et al
17060676	2006	ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer.	Locker GY et al
26405511	2015	Role of cytokines in Trypanosoma brucei-induced anaemia: A review of the literature.	Musaya J et al
7863218	1995	From genes to proteins: the nonspecific cross-reacting antigens.	Nagel G et al
3399813	1988	Immunohistochemistry of carcino-embryonic antigen in the embryo, fetus and adult.	Nap M et al
3510076	1986	Immunohistochemical localization of placental alkaline phosphatase, carcinoembryonic antigen, and cancer antigen 125 in normal and neoplastic human lung.	Nouwen EJ et al
1497672	1992	Homotypic and heterotypic Ca(++)-independent cell adhesion activities of biliary glycoprotein, a member of carcinoembryonic antigen family, expressed on CHO cell surface.	Oikawa S et al
3814146	1987	Primary structure of human carcinoembryonic antigen (CEA) deduced from cDNA sequence.	Oikawa S et al
24858421	2014	A comprehensive phylogenetic and structural analysis of the carcinoembryonic antigen (CEA) gene family.	Pavlopoulou A et al
22574157	2012	The CEA/CD3-bispecific antibody MEDI-565 (MT111) binds a nonlinear epitope in the full-length but not a short splice variant of CEA.	Peng L et al
8543780	1996	CD66a (BGP), an adhesion molecule of the carcinoembryonic antigen family, is expressed in epithelium, endothelium, and myeloid cells in a wide range of normal human tissues.	Prall F et al
8386136	1993	Definition of the expression of the human carcinoembryonic antigen and non-specific cross-reacting antigen in human breast and lung carcinomas.	Robbins PF et al
2342461	1990	Cloning of the complete gene for carcinoembryonic antigen: analysis of its promoter indicates a region conveying cell type-specific expression.	Schrewe H et al
7520463	1994	Monoclonal antibody COL-1 reacts with restricted epitopes on carcinoembryonic antigen: an immunohistochemical study.	Shi ZR et al
24740257	2014	Potent and specific antitumor effect of CEA-targeted photoimmunotherapy.	Shirasu N et al
26410860	2016	Acute and long-term effects of hyperbaric oxygen therapy on hemorheological parameters in patients with various disorders.	Sinan M et al
2842340	1988	Evidence for carboxyl-terminal processing and glycolipid-anchoring of human carcinoembryonic antigen.	Takami N et al
16778108	2006	Carcinoembryonic antigen-targeted selective gene therapy for gastric cancer through FZ33 fiber-modified adenovirus vectors.	Tanaka T et al
7806520	1994	CGM2, a member of the carcinoembryonic antigen gene family is down-regulated in colorectal carcinomas.	Thompson J et al
1941355	1991	Carcinoembryonic antigen gene family: molecular biology and clinical perspectives.	Thompson JA et al
3581081	1987	Structural studies of the carbohydrate moieties of carcinoembryonic antigens.	Yamashita K et al
7687926	1993	Specificity of anti-carcinoembryonic antigen monoclonal antibodies and their effects on CEA-mediated adhesion.	Zhou H et al

Other Information

Locus ID:

NCBI: 1048
MIM: 114890
HGNC: 1817
Ensembl: ENSG00000105388

Variants:

dbSNP: 1048
ClinVar: 1048
TCGA: ENSG00000105388
COSMIC: CEACAM5

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000105388	ENST00000221992	P06731
ENSG00000105388	ENST00000398599	P06731
ENSG00000105388	ENST00000405816	P06731
ENSG00000105388	ENST00000595113	M0R3J1
ENSG00000105388	ENST00000595403	M0QX98
ENSG00000105388	ENST00000615021	A0A087WYX0
ENSG00000105388	ENST00000616453	T2HUW8
ENSG00000105388	ENST00000617332	A0A024R0K5

Expression (GTEx)

100

150

200

250

300

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Post-translational modification: synthesis of GPI-anchored proteins	REACTOME	R-HSA-163125
Hemostasis	REACTOME	R-HSA-109582
Cell surface interactions at the vascular wall	REACTOME	R-HSA-202733

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37942534	2024	Detection and clinical significance of CEACAM5 methylation in colorectal cancer patients.	1
38502695	2024	Phenotypic screen of sixty-eight colorectal cancer cell lines identifies CEACAM6 and CEACAM5 as markers of acid resistance.	1
37942534	2024	Detection and clinical significance of CEACAM5 methylation in colorectal cancer patients.	1
38502695	2024	Phenotypic screen of sixty-eight colorectal cancer cell lines identifies CEACAM6 and CEACAM5 as markers of acid resistance.	1
37312199	2023	Combination of CEACAM5, EpCAM and CK19 gene expressions in mediastinal lymph node micrometastasis is a prognostic factor for non-small cell lung cancer.	1
37814871	2023	[Heterogeneity analysis of pancreatic cancer and identification of molecular subtypes of tumor cells based on CEACAM5, LGALS1 and CENPF gene expression].	0
37312199	2023	Combination of CEACAM5, EpCAM and CK19 gene expressions in mediastinal lymph node micrometastasis is a prognostic factor for non-small cell lung cancer.	1
37814871	2023	[Heterogeneity analysis of pancreatic cancer and identification of molecular subtypes of tumor cells based on CEACAM5, LGALS1 and CENPF gene expression].	0
33342327	2022	Molecular Nodal Restaging Based on CEACAM5, FGFR2b and PTPN11 Expression Adds No Relevant Clinical Information in Resected Non-Small Cell Lung Cancer.	1
34740610	2022	A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo.	11
35186129	2022	Clinical significance of tumor necrosis factor-alpha and carcinoembryonic antigen in gastric cancer.	6
36279687	2022	Differential expression of carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and dipeptidyl peptidase-4 (DPP4) with detection of Middle East respiratory syndrome-coronavirus in peripheral blood.	1
36377775	2022	CEACAM5 inhibits the lymphatic metastasis of head and neck squamous cell carcinoma by regulating epithelial-mesenchymal transition via inhibiting MDM2.	3
36494785	2022	Identification of CEACAM5 as a stemness-related inhibitory immune checkpoint in pancreatic cancer.	2
33342327	2022	Molecular Nodal Restaging Based on CEACAM5, FGFR2b and PTPN11 Expression Adds No Relevant Clinical Information in Resected Non-Small Cell Lung Cancer.	1

Citation

Naoto Shirasu ; Masahide Kuroki

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

Atlas Genet Cytogenet Oncol Haematol. 2015-08-01

Online version: http://atlasgeneticsoncology.org/gene/40047