MCID: ESP021
MIFTS: 80

Esophageal Cancer malady

Genetic diseases, Rare diseases, Cancer diseases, Gastrointestinal diseases, Skin diseases categories
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Summaries for Esophageal Cancer

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Sources:
8Disease Ontology, 43NIH Rare Diseases, 34MedlinePlus, 65Wikipedia, 47OMIM, 33MalaCards
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NIH Rare Diseases:43 Esophageal cancer is a cancer of the esophagus, the hollow tube that carries food and liquids from the throat to the stomach. as the cancer grows, symptoms may include painful or difficult swallowing, weight loss and coughing up blood. the exact cause is usually not known, but both environmental and genetic factors are throught to play a role in the development of this condition. in the united states, risk factors for developing esophageal cancer include smoking, heavy drinking, obesity, and damage from acid reflux. treatments include surgery, radiation, chemotherapy, and laser therapy. some patients may also need nutritional support, since the cancer or treatment may make it hard to swallow. last updated: 1/12/2012

MalaCards: Esophageal Cancer, also known as esophageal carcinoma, is related to gastric adenocarcinoma and adenocarcinoma, and has symptoms including endobrachyesophagus/barrett esophagus, lymphadenopathy/polyadenopathies and lymphadenopathy/polyadenopathies. An important gene associated with Esophageal Cancer is TGFBR2 (transforming growth factor, beta receptor II (70/80kDa)), and among its related pathways are IL-2 Gene Expression in Activated and Quiescent T-Cells and Cell cycle Regulation of G1 S transition part 1 . The drugs cisplatin and cisplatin pwdr and the compounds dl 111it and inostamycin have been mentioned in the context of this disorder. Affiliated tissues include the esophagus, lymph node and testes, and related mouse phenotypes are tumorigenesis and craniofacial.

Disease Ontology:8 A gastrointestinal system cancer that is located in the esophagus.

MedlinePlus:34 The esophagus is a hollow tube that carries food and liquids from your throat to your stomach. early esophageal cancer usually does not cause symptoms. later, you may have symptoms such as painful or difficult swallowing weight loss a hoarse voice or cough that doesn't go away you're at greater risk for getting esophageal cancer if you smoke, drink heavily, or have acid reflux. your risk also goes up as you age your doctor uses imaging tests and a biopsy to diagnose esophageal cancer. treatments include surgery, radiation, and chemotherapy. you might also need nutritional support, since the cancer or treatment may make it hard to swallow. nih: national cancer institute

Wikipedia:65 Esophageal cancer (or oesophageal cancer) is cancer arising from the esophagus?the foodpipe that runs... more...

Description from OMIM:47 133239

Aliases & Classifications for Esophageal Cancer

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Sources:
8Disease Ontology, 9diseasecard, 43NIH Rare Diseases, 47OMIM, 10DISEASES, 45Novoseek, 49Orphanet, 34MedlinePlus, 62UMLS, 58SNOMED-CT, 40NCIt, 35MeSH, 26ICD10 via Orphanet, 59SNOMED-CT via Orphanet, 63UMLS via Orphanet, 25ICD10
See all sources

Classifications:



Characteristics (Orphanet epidemiological data):

49
esophageal cancer:
Prevalence: 1-9/100000; Age of onset: Adulthood
esophageal squamous cell carcinoma:
Prevalence: 1-9/100000; Age of onset: Adulthood; Age of death: Adult


Aliases & Descriptions:

esophageal cancer 8 9 43 47 10 49 34
esophageal carcinoma 8 45 49 62
malignant neoplasm of middle third of esophagus 8 62
esophagus cancer 8 43
malignant tumor of the middle third of the esophagus 8
malignant neoplasm of proximal third of esophagus 8
malignant neoplasm of middle third of oesophagus 8
malignant neoplasm of distal third of esophagus 8
malignant neoplasm of lower third of oesophagus 8
malignant neoplasm of lower third of esophagus 8
malignant tumor of proximal third of esophagus 8
malignant neoplasm of upper third of esophagus 8
malignant tumor of distal third of esophagus 8
malignant tumor of middle third of esophagus 8
malignant neoplasm of upper third esophagus 8
malignant tumor of lower third of esophagus 8
malignant tumor of upper third of esophagus 8
malignant neoplasm of abdominal oesophagus 8
malignant neoplasm of abdominal esophagus 8
malignant tumor of abdominal esophagus 8
squamous cell carcinoma of esophagus 62
esophageal squamous cell carcinoma 49
esophageal epidermoid carcinoma 49
malignant neoplasm of esophagus 62
ca middle third oesophagus 8
ca lower third oesophagus 8
ca middle third esophagus 8
ca lower third esophagus 8
carcinoma of oesophagus 8
carcinoma of esophagus 8
cancer of oesophagus 8
esophageal neoplasms 62
malignant neoplasms 62
cancer of esophagus 8


External Ids:

Disease Ontology8 DOID:5041, DOID:1107
NCIt40 C3028, C3513
MeSH35 D004938
OMIM47 133239
ICD10 via Orphanet26 C15
SNOMED-CT via Orphanet59 372138000, 276804009
UMLS via Orphanet63 C0152018
ICD1025 C15, C15.4, C15.5

Related Diseases for Esophageal Cancer

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Sources:
17GeneCards, 18GeneDecks
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Diseases related to Esophageal Cancer via text searches within MalaCards or GeneCards/GeneDecks gene sharing:

(show top 50)    (show all 168)
idRelated DiseaseScoreTop Affiliating Genes
1gastric adenocarcinoma31.1GSTM1, BAX, KLF4
2adenocarcinoma30.6TGFBR2, TOP1, CCND1, ALDH2, GSTM1, RARB
3esophageal squamous cell carcinoma30.6DEC1, LZTS1
4retinoblastoma30.4TGFBR2, CCND1, RARB, BAX, CDK4
5non-small cell lung carcinoma30.4TGFBR2, TOP1, CCND1, GSTM1, RARB, BAX
6lung cancer30.4TGFBR2, TOP1, GSTM1, RARB, BAX, CDK4
7oral leukoplakia30.4RARB, GSTM1
8leukoplakia30.3RARB, GSTM1
9colorectal cancer30.2TGFBR2, TOP1, CCND1, BAX, CDK4
10lung adenocarcinoma30.0TGFBR2, TOP1, CCND1, GSTM1, RARB, BAX
11cervical cancer30.0TGFBR2, GSTM1, RARB, BAX, CDK4
12stomach cancer30.0TGFBR2, CCND1, ALDH2, RARB, BAX
13squamous cell carcinoma of the head and neck30.0TGFBR2, CCND1, ALDH2, GSTM1, RARB, CDK4
14melanoma30.0TOP1, CCND1, RARB, BAX, CDK4
15colon cancer29.9TGFBR2, TOP1, CCND1, RARB, BAX, CDK4
16leukemia29.9TOP1, CCND1, ALDH2, GSTM1, RARB, BAX
17hepatocellular carcinoma29.9TGFBR2, CCND1, ALDH2, DLC1, GSTM1, RARB
18esophagitis11.5
19gastric cardia adenocarcinoma10.6
20tylosis with esophageal cancer10.5
21barrett's esophagus10.5
22endotheliitis10.5
23small cell carcinoma10.5
24right aortic arch10.4
25atrophic gastritis10.4
26gastritis10.4
27esophageal squamous cell carcinoma, somatic10.4
28dysphagia10.4
29esophageal cancer, somatic10.4
30cervicitis10.3
31tracheoesophageal fistula10.3
32squamous cell papilloma10.2
33iritis10.2
34pemphigus10.2
35eosinophilic esophagitis10.2
36gastric cardia carcinoma10.2
37laryngitis10.2
38leiomyoma10.2
39lipoma10.2
40scleroderma10.2
41syncope10.2
42xeroderma pigmentosum, group a10.2
43paraneoplastic pemphigus10.2
44esophagus squamous cell carcinoma10.2
45achalasia10.2
46situs inversus10.2
47tracheal stenosis10.2
48candidiasis10.2
49obesity10.2
50esophageal cancer, childhood10.2

Graphical network of the top 20 diseases related to Esophageal Cancer:



Diseases related to esophageal cancer

Symptoms for Esophageal Cancer

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Sources:
47OMIM, 49Orphanet
See all sources


Clinical features from OMIM:

133239

Symptoms:

49 (show all 14)
  • endobrachyesophagus/barrett esophagus
  • lymphadenopathy/polyadenopathies
  • nausea/vomiting/regurgitation/merycism/hyperemesis
  • feeding disorder/dysphagia/swallowing/sucking disorder/esophageal dyskinesia
  • chronic hiccup
  • gastroesophageal reflux/pyrosis/esophagitis/hiatal hernia/gastroparesia
  • abnormal cry/voice/phonation disorder/nasal speech
  • weight loss/loss of appetite/break in weight curve/general health alteration
  • thoracic/chest pain
  • cough
  • intestinal/colonic anomaly
  • anomalies of the neck
  • esophageal neoplasm/tumor/carcinoma/cancer
  • generalized obesity

Drugs & Therapeutics for Esophageal Cancer

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Sources:
42NIH Clinical Center, 6ClinicalTrials, 62UMLS, 41NDF-RT
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Drug clinical trials:

Search ClinicalTrials for Esophageal Cancer

Search NIH Clinical Center for Esophageal Cancer

Inferred drug relations via UMLS62/NDF-RT41:

Genetic Tests for Esophageal Cancer

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Anatomical Context for Esophageal Cancer

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Sources:
33MalaCards, 14FMA
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MalaCards organs/tissues related to Esophageal Cancer:

33
Lymph node, Testes, Lung, Endothelial, Colon, T cells, Breast, Bone marrow, Bone, Brain, Testis, Liver, Pituitary, Whole blood, Skeletal muscle, Thyroid, Prostate

FMA organs/tissues related to Esophageal Cancer:

14
The esophagus

Animal Models for Esophageal Cancer or affiliated genes

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Sources:
37MGI
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Publications for Esophageal Cancer

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Sources:
52PubMed
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Articles related to Esophageal Cancer:

(show top 50)    (show all 1196)
idTitleAuthorsYear
1
Randomized study of antiinflammatory and immune-modulatory effects of enteral immunonutrition during concurrent chemoradiotherapy for esophageal cancer. (24274379)
2014
2
Patterns and trends in esophageal cancer mortality and incidence in Europe (1980-2011) and predictions to 2015. (24356640)
2014
3
Epigenetic silencing of checkpoint with fork-head associated and ring finger gene expression in esophageal cancer. (24348823)
2014
4
Nomogram for predicting the benefit of neoadjuvant chemoradiotherapy for patients with esophageal cancer: A SEER-Medicare analysis. (24194477)
2013
5
Metallic expandable stents in the management of malignant tracheal stenosis due to esophageal cancer with lymph node metastasis. (24179541)
2013
6
Treatment and outcome of young patients with esophageal cancer in the Netherlands. (24338660)
2013
7
Esophageal cancer awareness in Bomet district, Kenya. (23658578)
2013
8
Present status and progress of neoadjuvant chemoradiotherapy for esophageal cancer. (23681891)
2013
9
Clinical and oncological effects of triplet chemotherapy followed by radical esophagectomy for resectable esophageal cancer associated with unfavorable prognostic factors. (23963503)
2013
10
Detection of interfraction displacement and volume variance during radiotherapy of primary thoracic esophageal cancer based on repeated four-dimensional CT scans. (24074144)
2013
11
Fish consumption and risk of esophageal cancer and its subtypes: a systematic review and meta-analysis of observational studies. (23321574)
2013
12
Frequency of Lymph Node Metastasis in Submucosal Esophageal Cancer. (24169170)
2013
13
Trihalomethanes in drinking water and the risk of death from esophageal cancer: does hardness in drinking water matter? (23294300)
2013
14
Robotic-assisted totally transhiatal lymphadenectomy in the middle mediastinum for esophageal cancer. (24273609)
2013
15
Relationship between HLA-G gene polymorphism and the susceptibility of esophageal cancer in Kazakh and Han nationality in Xinjiang. (22080860)
2012
16
Positron emission tomography/computed tomography and esophageal cancer in the clinical practice: How does it affect the prognosis? (23361284)
2012
17
XAF1 is frequently methylated in human esophageal cancer. (22719195)
2012
18
Mechanism of loss of human esophageal cancer-related gene 4 (ECRG4) gene expression in esophageal squamous cell carcinoma cell line EC9706]. (22325214)
2011
19
Inhibition of PDK1 gene expression in esophageal cancer EC9706 cells by RNA interference and its effect on their malignant biological behavior]. (21875479)
2011
20
Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. (21533613)
2011
21
Deleted in Esophageal Cancer 1(DEC1) is down-regulated and contributes to migration in head and neck squamous cell carcinoma cell lines. (20975315)
2011
22
RAD001 offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer. (20204306)
2010
23
Study on the association of cytochrome P450 polymorphisms and the risk of esophageal cancer: a meta-analysis]. (20193595)
2009
24
Role of mitochondrial DNA 4977-bp deletions in esophageal cancer susceptibility and prognosis in a northern Indian population. (19963120)
2009
25
Selection of a novel drug-response predictor in esophageal cancer: a novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response. (18202764)
2008
26
Epigenetic inactivation of the deleted in lung and esophageal cancer 1 gene in nasopharyngeal carcinoma. (17099870)
2007
27
Ataxia-telangiectasia mutated expression is associated with tobacco smoke exposure in esophageal cancer tissues and benzo[a]pyrene diol epoxide in cell lines. (17019709)
2007
28
Identification of alpha-actinin 4 and 67 kDa laminin receptor as stage-specific markers in esophageal cancer via proteomic approaches. (17960614)
2007
29
Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. (17363571)
2007
30
Duodenal reflux leads to down regulation of DNA mismatch repair pathway in an animal model of esophageal cancer. (17257966)
2007
31
Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones. (17876050)
2007
32
Esophageal cancer in a young woman with bulimia nervosa: a case report. (18047676)
2007
33
Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin. (17172403)
2006
34
Promoter methylation and response to chemotherapy and radiation in esophageal cancer. (16678495)
2006
35
Role for the double-stranded RNA-activated protein kinase PKR in Ad-TNF-alpha gene therapy in esophageal cancer. (16153435)
2005
36
Inhibitory effects of esophageal cancer related gene 2 on proliferation of human esophageal cancer cell EC9706]. (16324322)
2005
37
Relationship between glucose transporter, hexokinase and FDG-PET in esophageal cancer. (15816463)
2005
38
A case-control study on the polymorphisms of methylenetetrahydrofolate reductase 1298A-->C and susceptibility of esophageal cancer]. (15231206)
2004
39
Relationship between polymorphism of IRF-3 gene codon 427 and esophageal cancer in Anyang population of China]. (15303122)
2004
40
Vascular endothelial growth factor in esophageal cancer. (15282704)
2004
41
Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer. (15170665)
2004
42
Treatment of a patient with advanced esophageal cancer with a combination of mitomycin C and capecitabine: activation of the thymidine phosphorylase as active principle? (12771525)
2003
43
Polymorphisms and mutations found in the regions flanking exons 5 to 8 of the TP53 gene in a population at high risk for esophageal cancer in South Africa. (12550754)
2003
44
Serine proteinase activation in esophageal cancer. (11724279)
2001
45
Preclinical study of adenoviral p53 gene therapy for esophageal cancer. (11495154)
2001
46
Down-regulation of nerve growth factor in poorly differentiated and advanced human esophageal cancer. (10769644)
2000
47
Role of nutrition support during induction chemoradiation therapy in esophageal cancer. (9437649)
1998
48
ras mutation and expression of the ras-regulated genes osteopontin and cathepsin L in human esophageal cancer. (9311587)
1997
49
13-Cis-retinoic acid and interferon alpha-2a in patients with advanced esophageal cancer: a phase II trial. (9157075)
1996
50
Relation of epidermal growth factor receptor concentration to growth of human esophageal cancer cell lines. (8274053)
1993

Variations for Esophageal Cancer

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Sources:
64UniProtKB/Swiss-Prot, 1 National Center for Biotechnology Information (Clinvar)
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UniProtKB/Swiss-Prot genetic disease variations for Esophageal Cancer:

64
id Symbol AA change Variation ID SNP ID
1TGFBR2p.Glu526GlnVAR_015816

Clinvar genetic disease variations for Esophageal Cancer:

1
id Gene Name Type Significance SNP ID Assembly Location
1TGFBR2NM_003242.5(TGFBR2): c.1576G> C (p.Glu526Gln)single nucleotide variantPathogenicrs121918714GRCh37Chr 3, 30732963: 30732963

Expression for genes affiliated with Esophageal Cancer

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Sources:
2BioGPS, 15Gene Expression Omnibus DataSets
See all sources
Expression patterns in normal tissues for genes affiliated with Esophageal Cancer

Search GEO for disease gene expression data for Esophageal Cancer.

Pathways for genes affiliated with Esophageal Cancer

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Sources:
50PathCards, 53QIAGEN, 60Thomson Reuters, 30KEGG, 38NCBI BioSystems Database, 54R&D Systems, 57SinoBiological
See all sources

Pathways related to Esophageal Cancer according to GeneCards/GeneDecks:

(show all 16)
idSuper pathways (with members indented)ScoreTop Affiliating Genes
1
Show member pathways
10.3CCND1, TGFBR2
2
Show member pathways
Cell cycle Role of SCF complex in cell cycle regulation60
10.1CDK4, CCND1, TGFBR2
3
Show member pathways
10.1CDK4, CCND1, TGFBR2
410.1TGFBR2, CCND1, CDK4
510.1BAX, CCND1, TGFBR2
6
Show member pathways
Signal transduction PTEN pathway60
10.1TGFBR2, CCND1, BAX
7
Show member pathways
IL-9 Signaling Pathway38
Development Thrombopoietin regulated cell processes60
IL-7 Signaling Pathway38
Immune response IL 9 signaling pathway60
10.1CDK4, BAX, CCND1
8
Show member pathways
10.1CDK4, BAX, CCND1
9
Show member pathways
Prostate Cancer38
Integrated Cancer pathway38
Steroid Biosynthesis38
10.1CCND1, BAX, CDK4
10
Show member pathways
DNA damage response38
10.1CDK4, BAX, CCND1
1110.1CCND1, RARB, CDK4
12
Show member pathways
Toll-like receptor signaling pathway38
Regulation of toll-like receptor signaling pathway38
10.0CDK4, BAX, CCND1, TGFBR2
1310.0TGFBR2, CCND1, BAX, CDK4
1410.0TGFBR2, CCND1, BAX, CDK4
159.9TGFBR2, CCND1, RARB, BAX, CDK4
169.8CDK4, BAX, RARB, CCND1, TOP1

Compounds for genes affiliated with Esophageal Cancer

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Sources:
45Novoseek, 24HMDB, 29IUPHAR, 11DrugBank, 61Tocris Bioscience, 51PharmGKB
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Compounds related to Esophageal Cancer according to GeneCards/GeneDecks:

(show top 50)    (show all 87)
idCompoundScoreTop Affiliating Genes
1dl 111it4510.6CCND1, CDK4
2inostamycin4510.6CCND1, BAX
3perillic acid45 2411.6CCND1, ALDH2
4pyrene4510.5GSTM1, CDK4
5pga24510.5CCND1, CDK4
6gossypol4510.5CDK4, BAX, CCND1
7vinylchloride4510.5ALDH2, GSTM1
8ursolic acid4510.5BAX, CCND1, TOP1
9apigenin45 2911.5CDK4, BAX, CCND1
10olomoucine45 1111.5CCND1, BAX, CDK4
11acyclic retinoid4510.5CCND1, RARB
12indole-3-carbinol4510.5CCND1, BAX, CDK4
13sulforaphane4510.5BAX, GSTM1, CCND1
14ciglitazone45 2911.5BAX, RARB, CCND1
15benzo(a)pyrene4510.5CDK4, RARB, GSTM1
16depsipeptide4510.5TOP1, CCND1, BAX
17eb 108945 6111.5TGFBR2, CCND1, BAX, CDK4
18betacarotene4510.4RARB, GSTM1, ALDH2
19agarose4510.4TGFBR2, ALDH2, GSTM1, BAX
20bortezomib45 51 1112.4TOP1, CCND1, BAX
215-aza-2deoxycytidine4510.4TGFBR2, TOP1, DLEC1, RARB
22flavopiridol45 1111.4TOP1, CCND1, BAX, CDK4
23adpribose4510.4TOP1, CCND1, BAX, CDK4
24vincristine45 51 1112.4BAX, GSTM1, CCND1, TOP1
25bleomycin45 1111.4TGFBR2, TOP1, GSTM1
26gefitinib45 51 1112.4TOP1, CCND1, CDK4
274,6-diamidino-2-phenylindole4510.4TOP1, BAX
284-hydroxynonenal45 2411.3BAX, GSTM1, ALDH2
295fluorouracil4510.3TOP1, GSTM1, BAX, CDK4
3010-hydroxycamptothecin4510.3TOP1, BAX
31n-(4-hydroxyphenyl)retinamide4510.3CDK4, BAX, RARB, CCND1, TGFBR2
32agar4510.3TOP1, CCND1, RARB, CDK4
33ag-1264510.3CCND1, CDK4
34thymidylate4510.3TOP1, CCND1, GSTM1, BAX, CDK4
35retinoid4510.3CCND1, ALDH2, RARB, BAX, CDK4
36carboplatin45 51 1112.3TOP1, GSTM1, CDK4
37egcg4510.3CDK4, BAX, RARB, CCND1, TOP1
38butyrate4510.3CDK4, KLF4, BAX, CCND1
39vitamin d4510.3CDK4, RARB, GSTM1, TGFBR2
40doxorubicin45 51 1112.2TOP1, CCND1, GSTM1, BAX, CDK4
41berberine4510.2CCND1, CDK4
42paclitaxel45 51 1112.2CDK4, BAX, CCND1, TOP1
43cycloheximide4510.2TGFBR2, TOP1, CCND1, RARB, BAX, CDK4
44cisplatin45 51 61 1113.1TOP1, CCND1, GSTM1, RARB, BAX, CDK4
45oligonucleotide4510.1TGFBR2, CCND1, ALDH2, RARB, KLF4, CDK4
46estrogen4510.1TGFBR2, CCND1, GSTM1, RARB, BAX, CDK4
47retinoic acid45 2411.1TGFBR2, CCND1, ALDH2, RARB, BAX, CDK4
48ly2940024510.0CDK4, BAX, CCND1, TGFBR2
49pd 98,059459.8CCND1, BAX, KLF4, CDK4
50gemcitabine45 51 1111.8TOP1, CCND1, BAX

GO Terms for genes affiliated with Esophageal Cancer

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Sources:
16Gene Ontology
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Cellular components related to Esophageal Cancer according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1cyclin-dependent protein kinase holoenzyme complexGO:00030710.2CDK4, CCND1

Biological processes related to Esophageal Cancer according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1negative regulation of cell cycle arrestGO:07115710.2CDK4, CCND1
2organ regenerationGO:03110010.1TGFBR2, CCND1, CDK4
3negative regulation of cell proliferationGO:0082859.9KLF4, RARB, DLEC1, DLC1, DEC1
4positive regulation of G2/M transition of mitotic cell cycleGO:0109719.9CDK4, CCND1
5response to drugGO:0424939.9TGFBR2, TOP1, CCND1, CDK4

Molecular functions related to Esophageal Cancer according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1protein complex bindingGO:03240310.1CDK4, RARB, CCND1

Products for genes affiliated with Esophageal Cancer

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  • Antibodies
  • Proteins
  • Lysates
  • Antibodies

Sources for Esophageal Cancer

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4CDC
13ExPASy
14FMA
22GTR
23HGMD
24HMDB
25ICD10
26ICD10 via Orphanet
27ICD9CM
29IUPHAR
30KEGG
35MeSH
36MESH via Orphanet
37MGI
40NCIt
41NDF-RT
44NINDS
45Novoseek
47OMIM
48OMIM via Orphanet
52PubMed
53QIAGEN
59SNOMED-CT via Orphanet
62UMLS
63UMLS via Orphanet