DCC (deleted in colorectal carcinoma)

2010-01-01 Sarah Derks , Manon van Engeland Affiliation

Department of Internal Medicine, Maastricht University Medical Center, PO BOX 616, 6200 MD Maastricht, The Netherlands (SD); Department of Pathology, Maastricht University Medical Center, PO BOX 616, 6200 MD Maastricht, The Netherlands (MvE)

Identity

HGNC

DCC

LOCATION

18q21.2

IMAGE

LEGEND

Diagram of chromosomal region 18q21.

LOCUSID

1630

ALIAS

CRC18,CRCR1,HGPPS2,IGDCC1,MRMV1,NTN1R1

FUSION GENES

Show Gene Fusions

DNA/RNA

Diagram of the DCC gene. Blue boxes represent exons.

Description

The DCC gene is composed of 29 exons spanning in a region of 1.2 million bp. The promoter contains a CpG island located -72 bp to +217 bp relative to the transcription startsite.

Transcription

The complete transcribed mRNA is 5693 bp long.

Splice variants:
13 splice variants have been documented.

Proteins

Diagram of the DCC protein. Ig: immunoglobulin, Fn: fibronectin-type III, TM: transmembrane domain, ICD: intracellular domain.

Description

DCC encodes a 158.5 kDa Type I membrane protein of 1447 amino acids with an extracellular (1100 amino acids), transmembrane and cytoplasmic (325 amino acids) domain. The extracellular domain includes four immunoglobulin-like domains and six fibronectin type III-like motifs. The cytoplasmic domain is composed of three conserved domains named P1, P2 and P3.

Expression

Expression is detected in many tissues (testis, lung, colon, esophagus, skeletal muscle) but is highest in normal brain tissue. Most tissues express low levels of transcripts and proteins.

Localisation

Cell surface.

Function

DCC is a member of the immunoglobulin superfamily of cell adhesion molecules and acts as a transmembrane dependence receptor for netrins, key factors in the regulation of axon guidance during development of the central nerve system.
In response to netrin-1, DCC becomes tyrosine phosphorylated, localizes to lipid rafts and selectively interacts with the Src family kinases Fyn and Lck to mediate axon attraction.
Furthermore DCC induces apoptosis when unbound to its ligand netrin-1. The DCC cytoplasmic domain is required for the induction of apoptosis and contains a caspase cleavage site which is recognized by caspase 3 in vitro. Upstream of the caspase cleavage domain a proapoptotic domain named addiction dependence domain (ADD) is located, which interacts with caspase 9 in the absence of Netrin-1 and binds DCC-interacting protein-13a (DIP13-a) to mediate DCC-induced cell death.
DCCs downstream effects involve MAPK activation and subsequent activation of the transcription factor Elk-1 and SRE regulated gene expression.

Homology

DCC has a homolog in mammals named neogin and is conserved in chimpanzee, dog, cow, mouse, rat, zebrafish, Caenorhabditis elegans (UNC40) and Drosophila (Frazzled).

Mutations

Somatic

DCC mutations rarely occur in cancer. In colorectal cancer (CRC) the most common somatic mutations are 120 to 300 bp expansions in a dinucleotide repeat tract located in an intron region immediately downstream of exon 7. Expansions are present in 10-15 % of CRCs which are cancers with microsatellite instability.

Implicated in

Entity name

Colorectal cancer

Note

By regulating apoptosis in the absence of netrin-1, DCC is a conditional tumor suppressor. In normal conditions, DCC induced apoptosis limits cellular lifespan in the intestinal crypt and thereby inhibits the initiation of malignant transformation. Transfection of DCC cDNA into a human cell line lacking DCC expression suppresses tumor growth and results in apoptosis and cell cycle arrest.
DCC is located on chromosomal region 18q21-pter which is affected by loss of heterozygosity (LOH) which is associated with reduced DCC expression in approximately 70% of colorectal cancers.
Although DCC mutation is rare, DCC promoter CpG island methylation occurs in about 80% of CRCs.

Prognosis

Absent DCC expression is a strong predictor of poor survival in stage II and stage III CRCs. In patients with stage II disease decreased DCC expression is associated with a five-year survival rate of 61.6% versus 94.3% in DCC expressing stage II CRCs. In patients with stage III disease, the respective survival rates are 59.3 percent and 33.2 percent. LOH of 18q21 alone was also associated with poor prognosis and risk of metastasis in some studies although this association was not observed by others.
Furthermore 18q LOH is associated with decreases responsiveness to fluorouracil-based adjuvant chemotherapy in stage III CRC.

Oncogenesis

LOH of chromosome 18q21 profoundly occurs in progressed adenomas and colorectal carcinomas and is present in about 100% of hepatic metastasis but rarely occurs in early stage lesions. The same accounts for DCC promoter CpG island methylation which is present in 80% of adenomas and carcinomas and in only 23% of normal colon tissues.

Entity name

Gastric cancer

Note

Reduced DCC mRNA expression is observed in 52% of gastric cancers, being present in 72% of intestinal type gastric cancers and in 17% of infiltrative type gastric cancers.
LOH of 18q21 occurs in 30% of intestinal type gastric cancers and is an infrequent event in early or advanced gastric cancer.

Oncogenesis

All liver metastasis of gastric carcinomas showed reduced DCC expression.

Entity name

Head and neck squamous cell carcinoma (HNSCC)

Note

DCC promoter CpG island methylation occurs in 75% of HNSCC. Restoration of DCC expression (by transfection) led to inhibition of cell growth in HNSCC cell lines.

Prognosis

LOH of chromosomal region 18q21 occurs in 40% of HNSCC and is associated with poor patient survival.

Entity name

Esophageal cancer

Note

18q21 LOH occurs in 23% of esophageal squamous cell carcinomas (ESCC). DCC promoter CpG island methylation occurs in 74% of primary ESCCs in a cancer-specific manner.
Sixty-nine percent of esophageal adenocarcinomas show LOH of 18q21.

Oncogenesis

18q21 LOH occurs in 32% of barrets mucosae, 42% of low-grade dysplastic lesions, 73% of high grade dysplastic lesions and 69% of adenocarcinomas.

Entity name

Glioma

Note

DCC expression is reduced in 66% of high-grade astrocytomas, 53% of secondary glioblastomas (progressed for low-grade astrocytomas) and 23% of de novo glioblastoma.
DCC expression is reduced in 88% of glioblastoma multiforme.

Oncogenesis

Only a minority (6%) of low-grade astrocytomas show reduced DCC expression, whereas high-grade tumors show reduces DCC expression in 66% of cases.

Entity name

Neuroblastoma

Note

Reduced DCC expression and 18q21 LOH occurs in 25-40% and 31% of primary neuroblastomas respectively.

Oncogenesis

In neuroblastomas decreased DCC expression increases from 25% in stage 1-3 to 72% in stage 4 disease to 81% in metastatic disease.

Entity name

Hematologic malignancies/Lymphoma

Note

DCC is inactivated in 30% of acute leukemias in 25% of chronic myelogenous leukemias (CML) and in 53% of non Hodgkins lymphoma.
In 18% of follicle centre cell lymphoma LOH of DCC is observed.

Entity name

Bladder cancer

Note

LOH of 18q21 occurs in 36% of bladder carcinomas and 33% of human bladder transitional cell carcinomas (TCCs).

Entity name

Breast cancer

Note

DCC expression is reduced in 40-55.6% of primary breast cancer.

Prognosis

DCC expression is associated with longer relapse free and overall survival.

Entity name

Prostate cancer

Note

Eighty-five percent of prostate cancers exhibit decrease DCC expression compared to normal tissue. 18q21 LOH occurs in 26-31% prostate cancers.

Entity name

Renal cancer

Note

DCC protein expression is reduced in 40% of clear cell renal cell carcinomas (cRCC) and LOH of 18q21 occurs in 19% of cRCC.
18q21 LOH is observed in 20% of nephroblastomas.

Prognosis

Decreased DCC protein expression occurred more frequently in patients who died from the disease (63%) compared to patients who did not (36%). 18q21 LOH in nephroblastomas is associated with poor prognosis.

Entity name

Ovarian cancer

Note

DCC mRNA expression is reduced in 60% of epithelial ovarian cancer and in 50% of serous ovarian cancers.

Prognosis

Reduced DCC expression is associated with poor patient outcome in epithelial ovarian cancer which is also observed in a cohort treated with combined chemotherapy platinum-paclitaxel.

Oncogenesis

Reduces DCC mRNA expression is reported in only 10% of ovarian adenomas and 6% of borderline tumors compared with 60% in ovarian carcinomas.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
16971669	2006	Automated quantitative analysis of DCC tumor suppressor protein in ovarian cancer tissue microarray shows association with beta-catenin levels and outcome in patients with epithelial ovarian cancer.	Bamias A et al
12901278	2003	Prognostic significance of the deleted in colorectal cancer gene protein expression in high-risk resected gastric carcinoma.	Bamias AT et al
7510345	1994	Somatic allelic loss at the DCC, APC, nm23-H1 and p53 tumor suppressor gene loci in human prostatic carcinoma.	Brewster SF et al
11304690	2001	Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18.	Büschges R et al
9609755	1998	Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer.	Carethers JM et al
17018594	2006	Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma.	Carvalho AL et al
8188295	1994	The DCC gene: structural analysis and mutations in colorectal carcinomas.	Cho KR et al
15050007	2004	DCC protein expression in clear cell renal cell carcinoma.	Dekel Y et al
19329758	2009	Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21.	Derks S et al
11986622	2002	Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.	Forcet C et al
12770737	2003	Genetic alterations in ovarian carcinoma: with specific reference to histological subtypes.	Fujita M et al
8504411	1993	Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostatic carcinomas.	Gao X et al
16337851	2005	Deletion mapping of 18q in conventional renal cell carcinoma.	Hirata H et al
10469217	1999	Reduced expression of APC and DCC gene protein in breast cancer.	Ho KY et al
1423299	1992	Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers.	Huang Y et al
8015568	1994	Allelic loss of chromosome 18q and prognosis in colorectal cancer.	Jen J et al
15491747	2004	Expression of DCC and netrin-1 in normal human endometrium and its implication in endometrial carcinogenesis.	Kato HD et al
7731713	1995	The DCC gene suppresses the malignant phenotype of transformed human epithelial cells.	Klingelhutz AJ et al
12908825	2003	The expression of DCC protein in female breast cancer.	Koren R et al
12471613	2003	Quantification of expression of netrins, slits and their receptors in human prostate tumors.	Latil A et al
12011067	2002	Mediation of the DCC apoptotic signal by DIP13 alpha.	Liu J et al
11387206	2001	Netrin-1 acts as a survival factor via its receptors UNC5H and DCC.	Llambi F et al
7674315	1995	Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.	Marra G et al
15343335	2004	Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.	Mazelin L et al
9796814	1998	The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.	Mehlen P et al
8187090	1994	Point mutations and allelic deletion of tumor suppressor gene DCC in human esophageal squamous cell carcinomas and their relation to metastasis.	Miyake S et al
8632608	1996	Loss of heterozygosity at the p53, RB, DCC and APC tumor suppressor gene loci in human bladder cancer.	Miyamoto H et al
18302152	2008	DCC promoter hypermethylation in esophageal squamous cell carcinoma.	Park HL et al
9559345	1998	Loss of 18q predicts poor survival of patients with squamous cell carcinoma of the head and neck.	Pearlstein RP et al
8490178	1993	DCC tumor suppressor gene is inactivated in hematologic malignancies showing monosomy 18.	Porfiri E et al
8580831	1995	DCC (deleted in colorectal cancer) inactivation in hematological malignancies.	Porfiri E et al
14631365	2004	Microsatellite analysis of the DCC gene in nephroblastomas: pathologic correlations and prognostic implications.	Ramburan A et al
8724537	1996	Allele imbalance at tumour suppressor loci during the indolent phase of follicle centre cell lymphoma.	Randerson J et al
9816273	1996	Loss of DCC expression in neuroblastoma is associated with disease dissemination.	Reale MA et al
18253061	2008	Tyrosine phosphorylation of netrin receptors in netrin-1 signaling.	Ren XR et al
9645757	1998	Status of deleted in colorectal cancer gene expression correlates with neuroblastoma metastasis.	Reyes-Mugica M et al
10682668	2000	Loss of DCC gene expression during ovarian tumorigenesis: relation to tumour differentiation and progression.	Saegusa M et al
8242611	1993	Expression of the tumor suppressor gene DCC in human gliomas.	Scheck AC et al
8929264	1996	The DCC protein and prognosis in colorectal cancer.	Shibata D et al
7478611	1995	Allelotype of neuroblastoma.	Takita J et al
11309634	2001	Molecular predictors of survival after adjuvant chemotherapy for colon cancer.	Watanabe T et al
9136822	1997	Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection.	Wu MS et al
9665490	1998	Genetic alterations in Barrett esophagus and adenocarcinomas of the esophagus and esophagogastric junction region.	Wu TT et al
7742542	1995	Decreased expression of the deleted in colorectal carcinoma gene in non-Hodgkin's lymphoma.	Younes A et al

Other Information

Locus ID:

NCBI: 1630
MIM: 120470
HGNC: 2701
Ensembl: ENSG00000187323

Variants:

dbSNP: 1630
ClinVar: 1630
TCGA: ENSG00000187323
COSMIC: DCC

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000187323	ENST00000304775	H0Y2Q5
ENSG00000187323	ENST00000412726	E7EQM8
ENSG00000187323	ENST00000442544	P43146
ENSG00000187323	ENST00000578080	J3QLT8
ENSG00000187323	ENST00000578949	J3QQJ6
ENSG00000187323	ENST00000579349	J3QRL3
ENSG00000187323	ENST00000579941	J3QRM6
ENSG00000187323	ENST00000581559	J3QLB0
ENSG00000187323	ENST00000581580	J3QS93
ENSG00000187323	ENST00000582875	J3QKL2

Expression (GTEx)

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
Axon guidance	KEGG	ko04360
Colorectal cancer	KEGG	ko05210
Axon guidance	KEGG	hsa04360
Pathways in cancer	KEGG	hsa05200
Colorectal cancer	KEGG	hsa05210
Cell-Cell communication	REACTOME	R-HSA-1500931
DSCAM interactions	REACTOME	R-HSA-376172
Programmed Cell Death	REACTOME	R-HSA-5357801
Apoptosis	REACTOME	R-HSA-109581
Caspase activation via extrinsic apoptotic signalling pathway	REACTOME	R-HSA-5357769
Ligand-independent caspase activation via DCC	REACTOME	R-HSA-418889
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
Netrin-1 signaling	REACTOME	R-HSA-373752
DCC mediated attractive signaling	REACTOME	R-HSA-418885
Netrin mediated repulsion signals	REACTOME	R-HSA-418886
Role of second messengers in netrin-1 signaling	REACTOME	R-HSA-418890

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38419228	2024	Identification of specific codon 201 mutation of the DCC Gene in the colonoscopic specimen of colorectal cancer.	0
38556604	2024	NME1 and DCC variants are associated with susceptibility and tumor characteristics in Mexican patients with colorectal cancer.	0
38419228	2024	Identification of specific codon 201 mutation of the DCC Gene in the colonoscopic specimen of colorectal cancer.	0
38556604	2024	NME1 and DCC variants are associated with susceptibility and tumor characteristics in Mexican patients with colorectal cancer.	0
36852451	2023	An imbalance of netrin-1 and DCC during nigral degeneration in experimental models and patients with Parkinson's disease.	2
36889039	2023	Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.	2
36852451	2023	An imbalance of netrin-1 and DCC during nigral degeneration in experimental models and patients with Parkinson's disease.	2
36889039	2023	Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.	2
34259111	2022	Genetic Susceptibility of DCC Gene in Gallbladder Cancer in Kashmir and Meta-Analysis.	2
34875255	2022	Association between serum netrin-1, netrin-4 and risk of the acute coronary syndrome in patients with type 2 diabetes mellitus-A pilot study.	0
35388180	2022	Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children.	5
34259111	2022	Genetic Susceptibility of DCC Gene in Gallbladder Cancer in Kashmir and Meta-Analysis.	2
34875255	2022	Association between serum netrin-1, netrin-4 and risk of the acute coronary syndrome in patients with type 2 diabetes mellitus-A pilot study.	0
35388180	2022	Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children.	5
33141514	2021	A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development.	2

Citation

Sarah Derks ; Manon van Engeland

DCC (deleted in colorectal carcinoma)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/331