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DCC (deleted in colorectal carcinoma)

Written2010-01Sarah Derks, Manon van Engeland
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)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesDCC subclass
member 1
Alias_symbol (synonym)IGDCC1
NTN1R1
Other aliasCRC18
CRCR1
HGNC (Hugo) DCC
LocusID (NCBI) 1630
Atlas_Id 331
Location 18q21.2  [Link to chromosome band 18q21]
Location_base_pair Starts at 52340172 and ends at 53535903 bp from pter ( according to hg19-Feb_2009)  [Mapping DCC.png]
Local_order Between RKHD2 and MBD2 genes.
 
  Diagram of chromosomal region 18q21.
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CYB5A (18q22.3) / DCC (18q21.2)DCC (18q21.2) / DCC (18q21.2)KCNMA1 (10q22.3) / DCC (18q21.2)
KIAA1328 (18q12.2) / DCC (18q21.2)ROCK1 (18q11.1) / DCC (18q21.2)

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.

Protein

 
  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

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

Bibliography

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PMID 19329758
 
Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.
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Nature. 2002 May 23;417(6887):443-7. Epub 2002 May 1.
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Mol Cell Endocrinol. 2003 Apr 28;202(1-2):97-9. (REVIEW)
PMID 12770737
 
Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostatic carcinomas.
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Cancer Res. 1993 Jun 15;53(12):2723-7.
PMID 8504411
 
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PMID 10469217
 
Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers.
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PMID 1423299
 
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N Engl J Med. 1994 Jul 28;331(4):213-21.
PMID 8015568
 
Expression of DCC and netrin-1 in normal human endometrium and its implication in endometrial carcinogenesis.
Kato HD, Kondoh H, Inoue T, Asanoma K, Matsuda T, Arima T, Kato K, Yoshikawa T, Wake N.
Gynecol Oncol. 2004 Nov;95(2):281-9.
PMID 15491747
 
The DCC gene suppresses the malignant phenotype of transformed human epithelial cells.
Klingelhutz AJ, Hedrick L, Cho KR, McDougall JK.
Oncogene. 1995 Apr 20;10(8):1581-6.
PMID 7731713
 
The expression of DCC protein in female breast cancer.
Koren R, Dekel Y, Sherman E, Weissman Y, Dreznik Z, Klein B, Gal R.
Breast Cancer Res Treat. 2003 Jul;80(2):215-20.
PMID 12908825
 
Quantification of expression of netrins, slits and their receptors in human prostate tumors.
Latil A, Chene L, Cochant-Priollet B, Mangin P, Fournier G, Berthon P, Cussenot O.
Int J Cancer. 2003 Jan 20;103(3):306-15.
PMID 12471613
 
Mediation of the DCC apoptotic signal by DIP13 alpha.
Liu J, Yao F, Wu R, Morgan M, Thorburn A, Finley RL Jr, Chen YQ.
J Biol Chem. 2002 Jul 19;277(29):26281-5. Epub 2002 May 14.
PMID 12011067
 
Netrin-1 acts as a survival factor via its receptors UNC5H and DCC.
Llambi F, Causeret F, Bloch-Gallego E, Mehlen P.
EMBO J. 2001 Jun 1;20(11):2715-22.
PMID 11387206
 
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PMID 7674315
 
Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.
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Nature. 2004 Sep 2;431(7004):80-4.
PMID 15343335
 
The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.
Mehlen P, Rabizadeh S, Snipas SJ, Assa-Munt N, Salvesen GS, Bredesen DE.
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PMID 9796814
 
Point mutations and allelic deletion of tumor suppressor gene DCC in human esophageal squamous cell carcinomas and their relation to metastasis.
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Cancer Res. 1994 Jun 1;54(11):3007-10.
PMID 8187090
 
Loss of heterozygosity at the p53, RB, DCC and APC tumor suppressor gene loci in human bladder cancer.
Miyamoto H, Shuin T, Ikeda I, Hosaka M, Kubota Y.
J Urol. 1996 Apr;155(4):1444-7.
PMID 8632608
 
DCC promoter hypermethylation in esophageal squamous cell carcinoma.
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PMID 18302152
 
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PMID 8490178
 
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Br J Cancer. 2000 Feb;82(3):571-8.
PMID 10682668
 
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Cancer Res. 1993 Dec 1;53(23):5605-9.
PMID 8242611
 
The DCC protein and prognosis in colorectal cancer.
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N Engl J Med. 1996 Dec 5;335(23):1727-32.
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PMID 7478611
 
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N Engl J Med. 2001 Apr 19;344(16):1196-206.
PMID 11309634
 
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Gastroenterology. 1997 May;112(5):1457-65.
PMID 9136822
 
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PMID 9665490
 
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Blood. 1995 May 15;85(10):2813-6.
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Citation

This paper should be referenced as such :
Derks, S ; van, Engeland M
DCC (deleted in colorectal carcinoma)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(10):845-907.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/DCCID331ch18q21.html

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 5 ]
  Colon: Colorectal adenocarcinoma
Head and Neck: Epidermoid carcinoma
Testis: Germ cell tumors
Bone: Osteosarcoma
Squamous cell cancer

External links

Nomenclature
HGNC (Hugo)DCC   2701
Cards
AtlasDCCID331ch18q21
Entrez_Gene (NCBI)DCC  1630  DCC netrin 1 receptor
AliasesCRC18; CRCR1; IGDCC1; MRMV1; 
NTN1R1
GeneCards (Weizmann)DCC
Ensembl hg19 (Hinxton)ENSG00000187323 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000187323 [Gene_View]  chr18:52340172-53535903 [Contig_View]  DCC [Vega]
ICGC DataPortalENSG00000187323
TCGA cBioPortalDCC
AceView (NCBI)DCC
Genatlas (Paris)DCC
WikiGenes1630
SOURCE (Princeton)DCC
Genetics Home Reference (NIH)DCC
Genomic and cartography
GoldenPath hg38 (UCSC)DCC  -     chr18:52340172-53535903 +  18q21.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)DCC  -     18q21.2   [Description]    (hg19-Feb_2009)
EnsemblDCC - 18q21.2 [CytoView hg19]  DCC - 18q21.2 [CytoView hg38]
Mapping of homologs : NCBIDCC [Mapview hg19]  DCC [Mapview hg38]
OMIM114500   120470   133239   157600   
Gene and transcription
Genbank (Entrez)AK302643 AK310385 AW949550 BC036524 BC152808
RefSeq transcript (Entrez)NM_005215
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)DCC
Cluster EST : UnigeneHs.162025 [ NCBI ]
CGAP (NCI)Hs.162025
Alternative Splicing GalleryENSG00000187323
Gene ExpressionDCC [ NCBI-GEO ]   DCC [ EBI - ARRAY_EXPRESS ]   DCC [ SEEK ]   DCC [ MEM ]
Gene Expression Viewer (FireBrowse)DCC [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1630
GTEX Portal (Tissue expression)DCC
Human Protein AtlasENSG00000187323-DCC [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP43146   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP43146  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP43146
Splice isoforms : SwissVarP43146
PhosPhoSitePlusP43146
Domaine pattern : Prosite (Expaxy)FN3 (PS50853)    IG_LIKE (PS50835)   
Domains : Interpro (EBI)DCC    FN3_dom    Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub    Ig_sub2    Neogenin_C   
Domain families : Pfam (Sanger)fn3 (PF00041)    I-set (PF07679)    Neogenin_C (PF06583)   
Domain families : Pfam (NCBI)pfam00041    pfam07679    pfam06583   
Domain families : Smart (EMBL)FN3 (SM00060)  IG (SM00409)  IGc2 (SM00408)  
Conserved Domain (NCBI)DCC
DMDM Disease mutations1630
Blocks (Seattle)DCC
PDB (SRS)2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
PDB (PDBSum)2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
PDB (IMB)2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
PDB (RSDB)2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
Structural Biology KnowledgeBase2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
SCOP (Structural Classification of Proteins)2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
CATH (Classification of proteins structures)2ED7    2ED8    2ED9    2EDB    2EDD    2EDE    3AU4    4URT   
SuperfamilyP43146
Human Protein Atlas [tissue]ENSG00000187323-DCC [tissue]
Peptide AtlasP43146
HPRD00391
IPIIPI00016422   IPI00911076   IPI01012289   
Protein Interaction databases
DIP (DOE-UCLA)P43146
IntAct (EBI)P43146
FunCoupENSG00000187323
BioGRIDDCC
STRING (EMBL)DCC
ZODIACDCC
Ontologies - Pathways
QuickGOP43146
Ontology : AmiGOneuron migration  transmembrane signaling receptor activity  netrin receptor activity  protein binding  cytosol  plasma membrane  apoptotic process  axonogenesis  axon guidance  negative regulation of neuron projection development  integral component of membrane  spinal cord ventral commissure morphogenesis  axon  dorsal/ventral axon guidance  anterior/posterior axon guidance  netrin-activated signaling pathway  negative regulation of collateral sprouting  extrinsic apoptotic signaling pathway in absence of ligand  regulation of neuron death  negative regulation of dendrite development  
Ontology : EGO-EBIneuron migration  transmembrane signaling receptor activity  netrin receptor activity  protein binding  cytosol  plasma membrane  apoptotic process  axonogenesis  axon guidance  negative regulation of neuron projection development  integral component of membrane  spinal cord ventral commissure morphogenesis  axon  dorsal/ventral axon guidance  anterior/posterior axon guidance  netrin-activated signaling pathway  negative regulation of collateral sprouting  extrinsic apoptotic signaling pathway in absence of ligand  regulation of neuron death  negative regulation of dendrite development  
Pathways : KEGGAxon guidance    Pathways in cancer    Colorectal cancer   
REACTOMEP43146 [protein]
REACTOME PathwaysR-HSA-418890 [pathway]   
NDEx NetworkDCC
Atlas of Cancer Signalling NetworkDCC
Wikipedia pathwaysDCC
Orthology - Evolution
OrthoDB1630
GeneTree (enSembl)ENSG00000187323
Phylogenetic Trees/Animal Genes : TreeFamDCC
HOVERGENP43146
HOGENOMP43146
Homologs : HomoloGeneDCC
Homology/Alignments : Family Browser (UCSC)DCC
Gene fusions - Rearrangements
Fusion : MitelmanCYB5A/DCC [18q22.3/18q21.2]  [t(18;18)(q21;q22)]  
Fusion : MitelmanKIAA1328/DCC [18q12.2/18q21.2]  [t(18;18)(q12;q21)]  
Fusion : MitelmanROCK1/DCC [18q11.1/18q21.2]  [t(18;18)(q11;q21)]  
Fusion: TCGACYB5A 18q22.3 DCC 18q21.2 SKCM
Fusion: TCGAKIAA1328 18q12.2 DCC 18q21.2 BLCA
Fusion: TCGAROCK1 18q11.1 DCC 18q21.2 HNSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDCC [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DCC
dbVarDCC
ClinVarDCC
1000_GenomesDCC 
Exome Variant ServerDCC
ExAC (Exome Aggregation Consortium)ENSG00000187323
GNOMAD BrowserENSG00000187323
Genetic variants : HAPMAP1630
Genomic Variants (DGV)DCC [DGVbeta]
DECIPHERDCC [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisDCC 
Mutations
ICGC Data PortalDCC 
TCGA Data PortalDCC 
Broad Tumor PortalDCC
OASIS PortalDCC [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICDCC  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDDCC
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 DCC
DgiDB (Drug Gene Interaction Database)DCC
DoCM (Curated mutations)DCC (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)DCC (select a term)
intoGenDCC
NCG5 (London)DCC
Cancer3DDCC(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM114500    120470    133239    157600   
Orphanet19298   
MedgenDCC
Genetic Testing Registry DCC
NextProtP43146 [Medical]
TSGene1630
GENETestsDCC
Target ValidationDCC
Huge Navigator DCC [HugePedia]
snp3D : Map Gene to Disease1630
BioCentury BCIQDCC
ClinGenDCC
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1630
Chemical/Pharm GKB GenePA27170
Clinical trialDCC
Miscellaneous
canSAR (ICR)DCC (select the gene name)
Probes
Litterature
PubMed115 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineDCC
EVEXDCC
GoPubMedDCC
iHOPDCC
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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