Chromosomal and microsatellite instability in colorectal cancer (Homo sapiens)

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MSI Pathway Nucleus Colorectal epithelial cell Activating mutation Legend Inactivating mutation Suppressed apoptosis Loss of growth inhibitory effects of TGFb Defective apoptosis DNA damage Proliferation, survival, migration, invasion Apoptosis Arachidonic acid Wnt signaling PI3K P P MAP2K1 KRAS Apoptosis NTN1 CYCS PGH2 CASP3 DCC TP53 PI3K-Akt Signaling Pathway p53 Signaling TGF beta Pathway RALA RALB P P TGFBR1 TGFBR2 P CASP9 P BAD ARAF RAF1 BRAF TCF7 TCF7L2 TCF7L1 LEF1 CTNNB1 SMAD4 P P SMAD2 P P SMAD3 TGFB1 TGFB2 TGFB3 AKT1 AKT2 AKT3 BIRC5 MYC CCND1 MLH1 MSH2 BAX TGFBR2 MSH3 MSH6 CDKN1A DDB2 POLK BAK1 BAX GADD45A GADD45B GADD45G PMAIP1 BAD BBC3 BCL2L11 BCL2 P GSK3B AXIN1 AXIN2 APC APC2 CSNK1A1L CSNK1A1 P P P CTNNB1 RALGDS RAC1 RAC2 RAC3 RHOA MAPK8 MAPK9 MAPK10 P P MAPK1 P P MAPK3 P JUN P FOS P P MYC MAPK Signaling Cell cycle APPL1 CASP9 CASP3 Anti-apoptosis Proliferation Uncontrolled proliferation Increased survival Genomic instability Survival EXOC2 TBK1 REL Cell-survival Inflammation CIN Pathway PTGS2 PGE2 COX-2 Pathway Name: Chromosomal and microsatellite instability in colorectal cancer Organism: Homo sapiens


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

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Ontology Terms

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Bibliography

  1. Mazzoni SM, Fearon ER; ''AXIN1 and AXIN2 variants in gastrointestinal cancers.''; Cancer Lett, 2014 PubMed
  2. 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
  3. Pino MS, Chung DC; ''The chromosomal instability pathway in colon cancer.''; Gastroenterology, 2010 PubMed

History

View all...
RevisionActionTimeUserComment
97624view 01:53, 31 May 2018AMTanOntology Term : 'colorectal cancer' added !
97180view 04:48, 4 May 2018EgonwThis interaction is not a mim-conversion.
97139view 15:24, 30 April 2018Khanspersupdated lit refs
96883view 22:01, 17 April 2018Khanspersupdated layout
96457view 04:47, 15 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
96198view 12:06, 26 February 2018Khanspersmoved p53 signaling section
96163view 18:36, 21 February 2018KhanspersModified description
96162view 18:34, 21 February 2018KhanspersCOX-2 reference
96161view 18:32, 21 February 2018KhanspersAdded Cox-2 pathway
96156view 13:42, 21 February 2018KhanspersAdded information from Pino et al
96147view 17:21, 20 February 2018KhanspersModified description
96146view 17:10, 20 February 2018KhanspersModified description
96145view 17:08, 20 February 2018KhanspersTGFRB2 mutation
96144view 17:00, 20 February 2018KhanspersModified description
96143view 16:58, 20 February 2018KhanspersKRAS mutation
96142view 15:47, 20 February 2018Khanspersmutation information for KRAS
96141view 15:41, 20 February 2018KhanspersModified description
96140view 15:38, 20 February 2018KhanspersDCC mutation information added as comment
96139view 15:30, 20 February 2018Khanspersphosphorylation sites - work in progress
96138view 15:00, 20 February 2018Khanspersphosphorylation sites - work in progress
95986view 12:23, 12 February 2018KhanspersOntology Term : 'epithelial cell' added !
95985view 12:23, 12 February 2018KhanspersOntology Term : 'altered DNA repair pathway' added !
95984view 12:22, 12 February 2018KhanspersOntology Term : 'altered Wnt signaling pathway' added !
95983view 12:22, 12 February 2018KhanspersOntology Term : 'colorectal cancer pathway' added !
95982view 12:21, 12 February 2018KhanspersModified description
95981view 12:20, 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 Signaling PathwayPathwayWP4172 (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 PathwayPathwayWP366 (WikiPathways)
TGFB1GeneProductENSG00000105329 (Ensembl)
TGFB2GeneProductENSG00000092969 (Ensembl)
TGFB3GeneProductENSG00000119699 (Ensembl)
TGFBR1GeneProductENSG00000106799 (Ensembl)
TGFBR2GeneProductENSG00000163513 (Ensembl)
TP53GeneProductENSG00000141510 (Ensembl)
Wnt signalingPathway
p53 SignalingPathwayWP1743 (WikiPathways)

Annotated Interactions

<cite>No annotated interactions</cite>