Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2C1SHW)

• DOT Name: Netrin receptor DCC (DCC)
• Synonyms: Colorectal cancer suppressor; Immunoglobulin superfamily DCC subclass member 1; Tumor suppressor protein DCC
• Gene Name: DCC
• Related Disease:
  Esophageal squamous cell carcinoma
  Gallbladder cancer
  Mirror movements 1
  Mirror movements 1 and/or agenesis of the corpus callosum
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adenoma
  Breast cancer
  Breast carcinoma
  Cholangiocarcinoma
  Colorectal adenocarcinoma
  Colorectal neoplasm
  Endometrial carcinoma
  Eosinophilic esophagitis
  Gallbladder carcinoma
  Gaze palsy, familial horizontal, with progressive scoliosis 1
  Intellectual disability
  leukaemia
  Major depressive disorder
  Melanoma
  Mood disorder
  Neoplasm of esophagus
  Neuroblastoma
  Non-small-cell lung cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Ulcerative colitis
  Adult lymphoma
  Connective tissue disorder
  Corpus callosum, agenesis of
  Endometrial cancer
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Myelodysplastic syndrome
  Pancreatic cancer
  Pediatric lymphoma
  Schizophrenia
  Familial congenital mirror movements
  Kallmann syndrome
  Acute lymphocytic leukaemia
  Plasma cell myeloma
  Carcinoma
  Gastric neoplasm
  Gaze palsy, familial horizontal, with progressive scoliosis, 2
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Prostate cancer
  Colorectal cancer
  Esophageal cancer
• UniProt ID: DCC_HUMAN
• PDB ID: 2ED7; 2ED8; 2ED9; 2EDB; 2EDD; 2EDE; 3AU4; 4URT; 5X83
• Pfam ID: PF00041 ; PF07679 ; PF06583
• Sequence:
  MENSLRCVWVPKLAFVLFGASLFSAHLQVTGFQIKAFTALRFLSEPSDAVTMRGGNVLLD
  CSAESDRGVPVIKWKKDGIHLALGMDERKQQLSNGSLLIQNILHSRHHKPDEGLYQCEAS
  LGDSGSIISRTAKVAVAGPLRFLSQTESVTAFMGDTVLLKCEVIGEPMPTIHWQKNQQDL
  TPIPGDSRVVVLPSGALQISRLQPGDIGIYRCSARNPASSRTGNEAEVRILSDPGLHRQL
  YFLQRPSNVVAIEGKDAVLECCVSGYPPPSFTWLRGEEVIQLRSKKYSLLGGSNLLISNV
  TDDDSGMYTCVVTYKNENISASAELTVLVPPWFLNHPSNLYAYESMDIEFECTVSGKPVP
  TVNWMKNGDVVIPSDYFQIVGGSNLRILGVVKSDEGFYQCVAENEAGNAQTSAQLIVPKP
  AIPSSSVLPSAPRDVVPVLVSSRFVRLSWRPPAEAKGNIQTFTVFFSREGDNRERALNTT
  QPGSLQLTVGNLKPEAMYTFRVVAYNEWGPGESSQPIKVATQPELQVPGPVENLQAVSTS
  PTSILITWEPPAYANGPVQGYRLFCTEVSTGKEQNIEVDGLSYKLEGLKKFTEYSLRFLA
  YNRYGPGVSTDDITVVTLSDVPSAPPQNVSLEVVNSRSIKVSWLPPPSGTQNGFITGYKI
  RHRKTTRRGEMETLEPNNLWYLFTGLEKGSQYSFQVSAMTVNGTGPPSNWYTAETPENDL
  DESQVPDQPSSLHVRPQTNCIIMSWTPPLNPNIVVRGYIIGYGVGSPYAETVRVDSKQRY
  YSIERLESSSHYVISLKAFNNAGEGVPLYESATTRSITDPTDPVDYYPLLDDFPTSVPDL
  STPMLPPVGVQAVALTHDAVRVSWADNSVPKNQKTSEVRLYTVRWRTSFSASAKYKSEDT
  TSLSYTATGLKPNTMYEFSVMVTKNRRSSTWSMTAHATTYEAAPTSAPKDLTVITREGKP
  RAVIVSWQPPLEANGKITAYILFYTLDKNIPIDDWIMETISGDRLTHQIMDLNLDTMYYF
  RIQARNSKGVGPLSDPILFRTLKVEHPDKMANDQGRHGDGGYWPVDTNLIDRSTLNEPPI
  GQMHPPHGSVTPQKNSNLLVIIVVTVGVITVLVVVIVAVICTRRSSAQQRKKRATHSAGK
  RKGSQKDLRPPDLWIHHEEMEMKNIEKPSGTDPAGRDSPIQSCQDLTPVSHSQSETQLGS
  KSTSHSGQDTEEAGSSMSTLERSLAARRAPRAKLMIPMDAQSNNPAVVSAIPVPTLESAQ
  YPGILPSPTCGYPHPQFTLRPVPFPTLSVDRGFGAGRSQSVSEGPTTQQPPMLPPSQPEH
  SSSEEAPSRTIPTACVRPTHPLRSFANPLLPPPMSAIEPKVPYTPLLSQPGPTLPKTHVK
  TASLGLAGKARSPLLPVSVPTAPEVSEESHKPTEDSANVYEQDDLSEQMASLEGLMKQLN
  AITGSAF
• Function: Receptor for netrin required for axon guidance. Mediates axon attraction of neuronal growth cones in the developing nervous system upon ligand binding. Its association with UNC5 proteins may trigger signaling for axon repulsion. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand. Implicated as a tumor suppressor gene.
• Tissue Specificity: Found in axons of the central and peripheral nervous system and in differentiated cell types of the intestine. Not expressed in colorectal tumor cells that lost their capacity to differentiate into mucus producing cells.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
• Reactome Pathway:
  DSCAM interactions (R-HSA-376172)
  DCC mediated attractive signaling (R-HSA-418885)
  Netrin mediated repulsion signals (R-HSA-418886)
  Caspase activation via Dependence Receptors in the absence of ligand (R-HSA-418889)
  Role of second messengers in netrin-1 signaling (R-HSA-418890)
  Regulation of commissural axon pathfinding by SLIT and ROBO (R-HSA-428542)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Posttranslational Modification	[1]
Gallbladder cancer	DISXJUAF	Definitive	Biomarker	[2]
Mirror movements 1	DISGKNLN	Definitive	Autosomal dominant	[3]
Mirror movements 1 and/or agenesis of the corpus callosum	DISJ95WV	Definitive	Autosomal dominant	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[5]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[6]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[9]
Colorectal adenocarcinoma	DISPQOUB	Strong	Altered Expression	[10]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[11]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[12]
Eosinophilic esophagitis	DISR8WSB	Strong	Genetic Variation	[13]
Gallbladder carcinoma	DISD6ACL	Strong	Biomarker	[9]
Gaze palsy, familial horizontal, with progressive scoliosis 1	DIS4KXBA	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[15]
leukaemia	DISS7D1V	Strong	Genetic Variation	[16]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[17]
Melanoma	DIS1RRCY	Strong	Biomarker	[18]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[19]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[20]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[1]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[24]
Adult lymphoma	DISK8IZR	moderate	Genetic Variation	[25]
Connective tissue disorder	DISKXBS3	Moderate	Autosomal recessive	[26]
Corpus callosum, agenesis of	DISO9P40	moderate	Genetic Variation	[27]
Endometrial cancer	DISW0LMR	moderate	Altered Expression	[12]
Hepatitis C virus infection	DISQ0M8R	moderate	Biomarker	[28]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[28]
Myelodysplastic syndrome	DISYHNUI	moderate	Biomarker	[29]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[30]
Pediatric lymphoma	DIS51BK2	moderate	Genetic Variation	[25]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[31]
Familial congenital mirror movements	DISJLV92	Supportive	Autosomal dominant	[32]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[33]
Acute lymphocytic leukaemia	DISPX75S	Disputed	Genetic Variation	[16]
Plasma cell myeloma	DIS0DFZ0	Disputed	Genetic Variation	[34]
Carcinoma	DISH9F1N	Limited	Posttranslational Modification	[35]
Gastric neoplasm	DISOKN4Y	Limited	Genetic Variation	[36]
Gaze palsy, familial horizontal, with progressive scoliosis, 2	DISR37VH	Limited	Autosomal recessive	[37]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[38]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[39]
Prostate cancer	DISF190Y	Limited	Altered Expression	[23]
Colorectal cancer	DISNH7P9	No Known	Unknown	[26]
Esophageal cancer	DISGB2VN	No Known	Unknown	[40]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Netrin receptor DCC (DCC).	[41]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Netrin receptor DCC (DCC).	[42]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Netrin receptor DCC (DCC).	[43]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Netrin receptor DCC (DCC).	[44]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Netrin receptor DCC (DCC).	[45]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Netrin receptor DCC (DCC).	[44]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Netrin receptor DCC (DCC).	[46]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Netrin receptor DCC (DCC).	[44]
Taxifolin	DMQJSF9	Preclinical	Taxifolin increases the expression of Netrin receptor DCC (DCC).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Netrin receptor DCC (DCC).	[50]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Netrin receptor DCC (DCC).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Netrin receptor DCC (DCC).	[49]

References

• [1] DCC promoter hypermethylation in esophageal squamous cell carcinoma.Int J Cancer. 2008 Jun 1;122(11):2498-502. doi: 10.1002/ijc.23434.
• [2] Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer.Ann Surg. 2014 Dec;260(6):1073-80. doi: 10.1097/SLA.0000000000000495.
• [3] Familial congenital mirror movements: report of a large 4-generation family. Neurology. 2009 Sep 1;73(9):729-31. doi: 10.1212/WNL.0b013e3181b59bda.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Identification of differentially methylated markers among cytogenetic risk groups of acute myeloid leukemia.Epigenetics. 2015;10(6):526-35. doi: 10.1080/15592294.2015.1048060.
• [6] Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma.J Gastrointest Surg. 2008 Oct;12(10):1664-72; discussion 1672-3. doi: 10.1007/s11605-008-0577-9. Epub 2008 Aug 2.
• [7] Colorectal cancer: genetics of development and metastasis.J Gastroenterol. 2006 Mar;41(3):185-92. doi: 10.1007/s00535-006-1801-6.
• [8] Genetic association of deleted in colorectal carcinoma variants with breast cancer risk: A case-control study.Oncotarget. 2016 May 31;7(22):32765-73. doi: 10.18632/oncotarget.9024.
• [9] Comparison of short- and long-term outcomes between anatomical subtypes of resected biliary tract cancer in a Western high-volume center.HPB (Oxford). 2020 Mar;22(3):405-414. doi: 10.1016/j.hpb.2019.07.011. Epub 2019 Sep 4.
• [10] Prognostic significance of the deleted in colorectal cancer gene protein expression in high-risk resected gastric carcinoma.Cancer Invest. 2003 Jun;21(3):333-40. doi: 10.1081/cnv-120018219.
• [11] Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer.Gastroenterology. 2007 Dec;133(6):1849-57. doi: 10.1053/j.gastro.2007.08.074. Epub 2007 Sep 5.
• [12] Expression of DCC and netrin-1 in normal human endometrium and its implication in endometrial carcinogenesis.Gynecol Oncol. 2004 Nov;95(2):281-9. doi: 10.1016/j.ygyno.2004.07.050.
• [13] Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.Nat Genet. 2014 Aug;46(8):895-900. doi: 10.1038/ng.3033. Epub 2014 Jul 13.
• [14] Biallelic mutations in human DCC cause developmental split-brain syndrome.Nat Genet. 2017 Apr;49(4):606-612. doi: 10.1038/ng.3804. Epub 2017 Feb 27.
• [15] Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.Nat Genet. 2017 Apr;49(4):511-514. doi: 10.1038/ng.3794. Epub 2017 Feb 27.
• [16] Expression of the DCC gene in human hematological malignancies.Leuk Lymphoma. 1994 Dec;16(1-2):13-8. doi: 10.3109/10428199409114135.
• [17] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [18] Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.Nat Genet. 2012 Sep;44(9):1006-14. doi: 10.1038/ng.2359. Epub 2012 Jul 29.
• [19] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [20] Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers.Cancer Res. 1992 Dec 1;52(23):6525-30.
• [21] Codon 201(Gly) polymorphic type of the DCC gene is related to disseminated neuroblastoma.Neoplasia. 2001 Jul-Aug;3(4):267-72. doi: 10.1038/sj.neo.7900169.
• [22] Mutation and expression of the DCC gene in human lung cancer.Neoplasia. 2000 Jul-Aug;2(4):300-5. doi: 10.1038/sj.neo.7900094.
• [23] Involvement of the multiple tumor suppressor genes and 12-lipoxygenase in human prostate cancer. Therapeutic implications.Adv Exp Med Biol. 1997;407:41-53. doi: 10.1007/978-1-4899-1813-0_7.
• [24] Associations between markers of colorectal cancer stem cells, mutation, microRNA and the clinical features of ulcerative colitis.Colorectal Dis. 2016 Jun;18(6):O185-93. doi: 10.1111/codi.13371.
• [25] Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing.Genet Med. 2015 Oct;17(10):831-5. doi: 10.1038/gim.2014.189. Epub 2015 Jan 8.
• [26] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [27] A novel heterozygous loss-of-function DCC Netrin 1 receptor variant in prenatal agenesis of corpus callosum and review of the literature.Am J Med Genet A. 2020 Jan;182(1):205-212. doi: 10.1002/ajmg.a.61404. Epub 2019 Nov 7.
• [28] Impact of All-Oral Direct-Acting Antivirals on Clinical and Economic Outcomes in Patients With Chronic Hepatitis C in the United States.Hepatology. 2019 Mar;69(3):1032-1045. doi: 10.1002/hep.30303. Epub 2019 Feb 10.
• [29] Alterations in the colorectal carcinoma gene and protein in a novel human myeloid leukemia cell line with trisomy 18 established from overt leukemia after myelodysplastic syndrome.Int J Hematol. 1998 Feb;67(2):153-64. doi: 10.1016/s0925-5710(97)00106-0.
• [30] Molecular biology of pancreatic cancer: potential clinical implications.BioDrugs. 2001;15(7):439-52. doi: 10.2165/00063030-200115070-00003.
• [31] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [32] Mutations in DCC cause congenital mirror movements. Science. 2010 Apr 30;328(5978):592. doi: 10.1126/science.1186463.
• [33] DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. Hum Mol Genet. 2018 Jan 15;27(2):359-372. doi: 10.1093/hmg/ddx408.
• [34] Downregulation of DCC sensitizes multiple myeloma cells to bortezomib treatment.Mol Med Rep. 2019 Jun;19(6):5023-5029. doi: 10.3892/mmr.2019.10142. Epub 2019 Apr 9.
• [35] Methylation of the DCC gene is lost in advanced gastric cancer.Anticancer Res. 2010 Jan;30(1):107-9.
• [36] The role of the Deleted Colon Cancer (DCC) gene in colorectal and gastric cancer.Cancer Invest. 2003 Jun;21(3):484-5. doi: 10.1081/cnv-120018241.
• [37] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [38] Loss of DCC expression and glioma progression.Cancer Res. 1997 Feb 1;57(3):382-6.
• [39] Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer.Oncotarget. 2016 May 3;7(18):26087-98. doi: 10.18632/oncotarget.8317.
• [40] Identification of rare germline copy number variations over-represented in five human cancer types. Mol Cancer. 2015 Feb 3;14:25. doi: 10.1186/s12943-015-0292-6.
• [41] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [42] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [43] Arsenic trioxide (As(2)O(3)) induced apoptosis and its mechanisms in a human esophageal squamous carcinoma cell line. Chin Med J (Engl). 2002 Feb;115(2):280-5.
• [44] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [45] 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. Carcinogenesis. 2009 Jun;30(6):1041-8. doi: 10.1093/carcin/bgp073. Epub 2009 Mar 27.
• [46] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [47] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [48] The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol Pharm Bull. 2007 Jun;30(6):1074-9.
• [49] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [50] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.