Chromosomal and microsatellite instability in colorectal cancer (Homo sapiens)

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354NucleusColorectal epithelial cellActivating mutationDefectiveapoptosisDNA damageMicrosatellite instability (MSI) pathwayProliferation, survival, migration, invasionLoss of growthinhibitory effects of TGFbLegendSuppressed apoptosisMLH1TGFB1ARAFApoptosisWnt signalingTCF7CDKN1ACYCSTGFBR1PI3K-Akt signalingCASP9NTN1BIRC5PMAIP1DCCPGH2p53 signalingMAP2K1SMAD2PI3KCASP3Arachidonic acidAKT1RALATGF-beta signalingBAXTP53KRASApoptosis2, 10PPPPP4TGFB2PPTGFB34TGFBR2SMAD3PPTGFBR2MSH3MSH6BCL2BADBBC3BCL2L11MSH2TCF7L2TCF7L1LEF1MYCCCND1GSK3BPAXIN1AXIN288RALGDSRAF1BRAFAKT2AKT3RALBRAC1RAC2RAC3RHOAMAPK8MAPK9MAPK10MAPK1PPMAPK3PPJUNFOSPMYCPPPBADPPMAPKsignalingCell cycleAPPL1CASP9CASP3DDB2POLKBAK1BAXGADD45AGADD45BGADD45GAPCAPC2Anti-apoptosisProliferationUncontrolled proliferationIncreased survivalGenomic instabilityInactivating mutationCSNK1A1LCSNK1A1CTNNB1PPPSurvivalEXOC2TBK1RELCell-survivalInflammationCTNNB1Chromosomal instability (CIN) pathwayPTGS24PGE2COX-2 pathwaySMAD41, 6, 9, 114


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

The most common mutation in colon cancer is inactivation of APC. When APC does not have an inactivating mutation, frequently there are activating mutations in β-catenin. In order for cancer to develop, both alleles must be mutated. Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutations, the risk of colorectal cancer by age 40 is almost 100%.

The impact of KRAS mutations is heavily dependent on the order of mutations. Primary KRAS mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previous APC mutation it often progresses to cancer. KRAS mutation is predictive of a very poor response to panitumumab and cetuximab therapy in colorectal cancer. Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%–50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab. Source: Wikipedia

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

de Miranda et al suggest that TGFβ signaling remains active in some CRC cells with MSI mutations in the TGFBR2 gene, because the mutated gene still expresses a functional protein.

Aberrant overexpression of cyclooxygenase-2 (COX-2) is thought to have an important role in development of CRC. The tumorigenic effects of COX-2 can be attributed to the production of PGE2; increased levels of PGE2 have been reported in colorectal adenomas as well as carcinomas. COX-2 and PGE2 regulate proliferation, survival, migration, and invasion in colorectal tumors. Source: Pino et al. Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Quality Tags

Ontology Terms

 

Bibliography

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  1. 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 Scholia
  2. 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 Scholia
  3. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E; ''PhosphoSitePlus, 2014: mutations, PTMs and recalibrations.''; Nucleic Acids Res, 2015 PubMed Europe PMC Scholia
  4. Pino MS, Chung DC; ''The chromosomal instability pathway in colon cancer.''; Gastroenterology, 2010 PubMed Europe PMC Scholia
  5. 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 Scholia
  6. 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 Scholia
  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 Scholia
  8. Mazzoni SM, Fearon ER; ''AXIN1 and AXIN2 variants in gastrointestinal cancers.''; Cancer Lett, 2014 PubMed Europe PMC Scholia
  9. Miyaki M, Kuroki T; ''Role of Smad4 (DPC4) inactivation in human cancer.''; Biochem Biophys Res Commun, 2003 PubMed Europe PMC Scholia
  10. 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 Scholia
  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 Scholia
  12. 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 Scholia

History

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CompareRevisionActionTimeUserComment
128152view16:40, 28 January 2024EweitzImprove alignment
128151view16:14, 28 January 2024EweitzImprove alignment, mitigate truncation
128150view13:18, 28 January 2024EweitzRefine legend
128149view13:09, 28 January 2024EweitzExpand key acronyms, standardize case
127498view18:49, 11 October 2023Khanspersupdated phosphosites for BAD
127314view23:03, 12 September 2023Khanspersupdated phosphosites
127238view20:19, 25 August 2023Khanspersadded lit ref and updated description
123363view05:04, 18 July 2022EgonwMade three pathways clickable
119088view05:27, 17 June 2021Khanspersupdated ptms
108124view10:27, 29 November 2019FehrhartOntology Term : 'cancer pathway' added !
106356view21:39, 21 August 2019KhanspersModified description
105505view05:57, 8 August 2019KhanspersModified description
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)
Arachidonic acidMetaboliteCHEBI:15843 (ChEBI)
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)
EXOC2GeneProductENSG00000112685 (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)
NTN1GeneProductENSG00000065320 (Ensembl)
PGE2MetaboliteQ416554 (Wikidata)
PGH2MetaboliteCHEBI:15554 (ChEBI)
PI3KGeneProduct
PI3K-Akt signalingPathwayWP4172 (WikiPathways)
PMAIP1GeneProductENSG00000141682 (Ensembl)
POLKGeneProductENSG00000122008 (Ensembl)
PTGS2GeneProductENSG00000073756 (Ensembl)
RAC1GeneProductENSG00000136238 (Ensembl)
RAC2GeneProductENSG00000128340 (Ensembl)
RAC3GeneProductENSG00000169750 (Ensembl)
RAF1GeneProductENSG00000132155 (Ensembl)
RALAGeneProductENSG00000006451 (Ensembl)
RALBGeneProductENSG00000144118 (Ensembl)
RALGDSGeneProductENSG00000160271 (Ensembl)
RELGeneProduct5966 (Entrez Gene)
RHOAGeneProductENSG00000067560 (Ensembl)
SMAD2GeneProductENSG00000175387 (Ensembl)
SMAD3GeneProductENSG00000166949 (Ensembl)
SMAD4GeneProductENSG00000141646 (Ensembl)
TBK1GeneProductENSG00000183735 (Ensembl)
TCF7GeneProductENSG00000081059 (Ensembl)
TCF7L1GeneProductENSG00000152284 (Ensembl)
TCF7L2GeneProductENSG00000148737 (Ensembl)
TGF-beta signalingPathwayWP366 (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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