Chromosomal and microsatellite instability in colorectal cancer (WP4216)

Homo sapiens

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


Kristina Hanspers , Egon Willighagen , Andika Tan , and Friederike Ehrhart


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Homo sapiens




Cell Type Ontology

epithelial cell

Pathway Ontology

altered Wnt signaling pathway altered DNA repair pathway colorectal cancer pathway cancer pathway

Disease Ontology

colorectal cancer


Label Type Compact Identifier Comment
Arachidonic acid Metabolite chebi:15843
PGH2 Metabolite chebi:15554
PGE2 Metabolite wikidata:Q416554
ARAF GeneProduct ensembl:ENSG00000078061
TGFBR1 GeneProduct ensembl:ENSG00000106799
SMAD2 GeneProduct ensembl:ENSG00000175387
MAP2K1 GeneProduct ensembl:ENSG00000169032
RALA GeneProduct ensembl:ENSG00000006451
TCF7 GeneProduct ensembl:ENSG00000081059
CDKN1A GeneProduct ensembl:ENSG00000124762
KRAS GeneProduct ensembl:ENSG00000133703
BIRC5 GeneProduct ensembl:ENSG00000089685
NTN1 GeneProduct ensembl:ENSG00000065320
CYCS GeneProduct ensembl:ENSG00000172115
AKT1 GeneProduct ensembl:ENSG00000142208
CASP3 GeneProduct ensembl:ENSG00000164305
DCC GeneProduct ensembl:ENSG00000187323
TGFB1 GeneProduct ensembl:ENSG00000105329
TP53 GeneProduct ensembl:ENSG00000141510
MLH1 GeneProduct ensembl:ENSG00000076242
CASP9 GeneProduct ensembl:ENSG00000132906
BAX GeneProduct ensembl:ENSG00000087088
PMAIP1 GeneProduct ensembl:ENSG00000141682
TGFB2 GeneProduct ensembl:ENSG00000092969
TGFB3 GeneProduct ensembl:ENSG00000119699
TGFBR2 GeneProduct ensembl:ENSG00000163513
SMAD3 GeneProduct ensembl:ENSG00000166949
TGFBR2 GeneProduct ensembl:ENSG00000163513
MSH3 GeneProduct ensembl:ENSG00000113318
MSH6 GeneProduct ensembl:ENSG00000116062
BCL2 GeneProduct ensembl:ENSG00000171791
BAD GeneProduct ensembl:ENSG00000002330
BBC3 GeneProduct ensembl:ENSG00000105327
BCL2L11 GeneProduct ensembl:ENSG00000153094
MSH2 GeneProduct ensembl:ENSG00000095002
TCF7L2 GeneProduct ensembl:ENSG00000148737
TCF7L1 GeneProduct ensembl:ENSG00000152284
LEF1 GeneProduct ensembl:ENSG00000138795
MYC GeneProduct ensembl:ENSG00000136997
CCND1 GeneProduct ensembl:ENSG00000110092
GSK3B GeneProduct ensembl:ENSG00000082701
AXIN1 GeneProduct ensembl:ENSG00000103126
AXIN2 GeneProduct ensembl:ENSG00000168646
RALGDS GeneProduct ensembl:ENSG00000160271
RAF1 GeneProduct ensembl:ENSG00000132155
BRAF GeneProduct ensembl:ENSG00000157764
AKT2 GeneProduct ensembl:ENSG00000105221
AKT3 GeneProduct ensembl:ENSG00000117020
RALB GeneProduct ensembl:ENSG00000144118
RAC1 GeneProduct ensembl:ENSG00000136238
RAC2 GeneProduct ensembl:ENSG00000128340
RAC3 GeneProduct ensembl:ENSG00000169750
RHOA GeneProduct ensembl:ENSG00000067560
MAPK8 GeneProduct ensembl:ENSG00000107643
MAPK9 GeneProduct ensembl:ENSG00000050748
MAPK10 GeneProduct ensembl:ENSG00000109339
MAPK1 GeneProduct ensembl:ENSG00000100030
MAPK3 GeneProduct ensembl:ENSG00000102882
JUN GeneProduct ensembl:ENSG00000177606
FOS GeneProduct ensembl:ENSG00000170345
MYC GeneProduct ensembl:ENSG00000136997
BAD GeneProduct ensembl:ENSG00000002330
APPL1 GeneProduct ensembl:ENSG00000157500
CASP9 GeneProduct ensembl:ENSG00000132906
CASP3 GeneProduct ensembl:ENSG00000164305
DDB2 GeneProduct ensembl:ENSG00000134574
POLK GeneProduct ensembl:ENSG00000122008
BAK1 GeneProduct ensembl:ENSG00000030110
BAX GeneProduct ensembl:ENSG00000087088
GADD45A GeneProduct ensembl:ENSG00000116717
GADD45B GeneProduct ensembl:ENSG00000099860
GADD45G GeneProduct ensembl:ENSG00000130222
APC GeneProduct ensembl:ENSG00000134982
APC2 GeneProduct ensembl:ENSG00000115266
CSNK1A1L GeneProduct ensembl:ENSG00000180138
CSNK1A1 GeneProduct ensembl:ENSG00000113712
CTNNB1 GeneProduct ensembl:ENSG00000168036
EXOC2 GeneProduct ensembl:ENSG00000112685
TBK1 GeneProduct ensembl:ENSG00000183735
REL GeneProduct ncbigene:5966
CTNNB1 GeneProduct ensembl:ENSG00000168036
PTGS2 GeneProduct ensembl:ENSG00000073756
SMAD4 GeneProduct ensembl:ENSG00000141646


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