Chromosomal and microsatellite instability in colorectal cancer (Homo sapiens)

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MSI Pathway1-22NucleusColorectal epithelial cellLoss of growthinhibitory effects of TGFbSuppressed apoptosisDNA damageActivating mutationDefectiveapoptosisLegendKRASBAXPMAIP1TCF7RALACDKN1API3K-Akt Signaling PathwayApoptosisp53 SignalingDCCARAFSMAD4ApoptosisMLH1AKT1SMAD2MAP2K1PI3KWnt signalingCYCSCASP9CASP3TGFBR1TGF beta PathwayTP53TGFB1BIRC5PPPTGFB2PPPPTGFB3TGFBR2SMAD3PPTGFBR2MSH3MSH6BCL2BADBBC3BCL2L11MSH2TCF7L2TCF7L1LEF1MYCCCND1GSK3BPAXIN1AXIN2RALGDSRAF1BRAFAKT2AKT3RALBRAC1RAC2RAC3RHOAMAPK8MAPK9MAPK10MAPK1PPMAPK3PPJUNFOSPPMYCPPBADPMAPKSignalingCell cycleAPPL1CASP9CASP3DDB2POLKBAK1BAXGADD45AGADD45BGADD45GAPCAPC2Anti-apoptosisProliferationUncontrolled proliferationIncreased survivalGenomic instabilityInactivating mutationCSNK1A1LCSNK1A1CTNNB1PPP


Description

CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC).

This pathway is based on information from KEGG

DCC can be considered a conditional tumor suppressor gene as well as a conditional oncogene. When DCC is present and not activated by netrin it is proapoptotic, and represses tumor formation. When DCC is present and netrin-activated it promotes cell survival, acting as an oncoprotein. One of the most frequent genetic abnormalities that occur in advanced colorectal cancer is loss of heterozygosity (LOH) of DCC in region 18q21. Source: Wikipedia

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Bibliography

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  1. Pino MS, Chung DC; ''The chromosomal instability pathway in colon cancer.''; Gastroenterology, 2010 PubMed Europe PMC
  2. Mazzoni SM, Fearon ER; ''AXIN1 and AXIN2 variants in gastrointestinal cancers.''; Cancer Lett, 2014 PubMed Europe PMC
  3. de Miranda NF, van Dinther M, van den Akker BE, van Wezel T, ten Dijke P, Morreau H; ''Transforming Growth Factor β Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2.''; Gastroenterology, 2015 PubMed Europe PMC
  4. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A; ''Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer.''; Pathol Res Pract, 2009 PubMed Europe PMC
  5. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD; ''Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.''; J Clin Oncol, 2008 PubMed Europe PMC
  6. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A; ''Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer.''; Pathol Res Pract, 2009 PubMed Europe PMC
  7. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD; ''Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.''; J Clin Oncol, 2008 PubMed Europe PMC
  8. De Bosscher K, Hill CS, Nicolás FJ; ''Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells.''; Biochem J, 2004 PubMed Europe PMC
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  10. Koyama M, Ito M, Nagai H, Emi M, Moriyama Y; ''Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.''; Mutat Res, 1999 PubMed Europe PMC
  11. Takagi Y, Kohmura H, Futamura M, Kida H, Tanemura H, Shimokawa K, Saji S; ''Somatic alterations of the DPC4 gene in human colorectal cancers in vivo.''; Gastroenterology, 1996 PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
103785view20:53, 5 April 2019KhanspersAdded lit refs
97624view08:53, 31 May 2018AMTanOntology Term : 'colorectal cancer' added !
97180view11:48, 4 May 2018EgonwThis interaction is not a mim-conversion.
97139view22:24, 30 April 2018Khanspersupdated lit refs
96883view05:01, 18 April 2018Khanspersupdated layout
96457view11:47, 15 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
96198view19:06, 26 February 2018Khanspersmoved p53 signaling section
96163view01:36, 22 February 2018KhanspersModified description
96162view01:34, 22 February 2018KhanspersCOX-2 reference
96161view01:32, 22 February 2018KhanspersAdded Cox-2 pathway
96156view20:42, 21 February 2018KhanspersAdded information from Pino et al
96147view00:21, 21 February 2018KhanspersModified description
96146view00:10, 21 February 2018KhanspersModified description
96145view00:08, 21 February 2018KhanspersTGFRB2 mutation
96144view00:00, 21 February 2018KhanspersModified description
96143view23:58, 20 February 2018KhanspersKRAS mutation
96142view22:47, 20 February 2018Khanspersmutation information for KRAS
96141view22:41, 20 February 2018KhanspersModified description
96140view22:38, 20 February 2018KhanspersDCC mutation information added as comment
96139view22:30, 20 February 2018Khanspersphosphorylation sites - work in progress
96138view22:00, 20 February 2018Khanspersphosphorylation sites - work in progress
95986view19:23, 12 February 2018KhanspersOntology Term : 'epithelial cell' added !
95985view19:23, 12 February 2018KhanspersOntology Term : 'altered DNA repair pathway' added !
95984view19:22, 12 February 2018KhanspersOntology Term : 'altered Wnt signaling pathway' added !
95983view19:22, 12 February 2018KhanspersOntology Term : 'colorectal cancer pathway' added !
95982view19:21, 12 February 2018KhanspersModified description
95981view19:20, 12 February 2018KhanspersNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
AKT2GeneProductENSG00000105221 (Ensembl)
AKT3GeneProductENSG00000117020 (Ensembl)
APC2GeneProductENSG00000115266 (Ensembl)
APCGeneProductENSG00000134982 (Ensembl)
APPL1GeneProductENSG00000157500 (Ensembl)
ARAFGeneProductENSG00000078061 (Ensembl)
AXIN1GeneProductENSG00000103126 (Ensembl)
AXIN2GeneProductENSG00000168646 (Ensembl)
ApoptosisPathway
ApoptosisPathwayWP254 (WikiPathways)
BADGeneProductENSG00000002330 (Ensembl)
BAK1GeneProductENSG00000030110 (Ensembl)
BAXGeneProductENSG00000087088 (Ensembl)
BBC3GeneProductENSG00000105327 (Ensembl)
BCL2GeneProductENSG00000171791 (Ensembl)
BCL2L11GeneProductENSG00000153094 (Ensembl)
BIRC5GeneProductENSG00000089685 (Ensembl)
BRAFGeneProductENSG00000157764 (Ensembl)
CASP3GeneProductENSG00000164305 (Ensembl)
CASP9GeneProductENSG00000132906 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl)
CDKN1AGeneProductENSG00000124762 (Ensembl)
CSNK1A1GeneProductENSG00000113712 (Ensembl)
CSNK1A1LGeneProductENSG00000180138 (Ensembl)
CTNNB1GeneProductENSG00000168036 (Ensembl)
CYCSGeneProductENSG00000172115 (Ensembl)
Cell cyclePathway
DCCGeneProductENSG00000187323 (Ensembl)
DDB2GeneProductENSG00000134574 (Ensembl)
FOSGeneProductENSG00000170345 (Ensembl)
GADD45AGeneProductENSG00000116717 (Ensembl)
GADD45BGeneProductENSG00000099860 (Ensembl)
GADD45GGeneProductENSG00000130222 (Ensembl)
GSK3BGeneProductENSG00000082701 (Ensembl)
JUNGeneProductENSG00000177606 (Ensembl)
KRASGeneProductENSG00000133703 (Ensembl)
LEF1GeneProductENSG00000138795 (Ensembl)
MAP2K1GeneProductENSG00000169032 (Ensembl)
MAPK SignalingPathway
MAPK10GeneProductENSG00000109339 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MAPK3GeneProductENSG00000102882 (Ensembl)
MAPK8GeneProductENSG00000107643 (Ensembl)
MAPK9GeneProductENSG00000050748 (Ensembl)
MLH1GeneProductENSG00000076242 (Ensembl)
MSH2GeneProductENSG00000095002 (Ensembl)
MSH3GeneProductENSG00000113318 (Ensembl)
MSH6GeneProductENSG00000116062 (Ensembl)
MYCGeneProductENSG00000136997 (Ensembl)
PI3KGeneProduct
PI3K-Akt Signaling PathwayPathwayWP4172 (WikiPathways)
PMAIP1GeneProductENSG00000141682 (Ensembl)
POLKGeneProductENSG00000122008 (Ensembl)
RAC1GeneProductENSG00000136238 (Ensembl)
RAC2GeneProductENSG00000128340 (Ensembl)
RAC3GeneProductENSG00000169750 (Ensembl)
RAF1GeneProductENSG00000132155 (Ensembl)
RALAGeneProductENSG00000006451 (Ensembl)
RALBGeneProductENSG00000144118 (Ensembl)
RALGDSGeneProductENSG00000160271 (Ensembl)
RHOAGeneProductENSG00000067560 (Ensembl)
SMAD2GeneProductENSG00000175387 (Ensembl)
SMAD3GeneProductENSG00000166949 (Ensembl)
SMAD4GeneProductENSG00000141646 (Ensembl)
TCF7GeneProductENSG00000081059 (Ensembl)
TCF7L1GeneProductENSG00000152284 (Ensembl)
TCF7L2GeneProductENSG00000148737 (Ensembl)
TGF beta PathwayPathwayWP366 (WikiPathways)
TGFB1GeneProductENSG00000105329 (Ensembl)
TGFB2GeneProductENSG00000092969 (Ensembl)
TGFB3GeneProductENSG00000119699 (Ensembl)
TGFBR1GeneProductENSG00000106799 (Ensembl)
TGFBR2GeneProductENSG00000163513 (Ensembl)
TP53GeneProductENSG00000141510 (Ensembl)
Wnt signalingPathway
p53 SignalingPathwayWP1743 (WikiPathways)

Annotated Interactions

No annotated interactions

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