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This KEGG map traces the step-by-step genetic route from normal bowel lining to colorectal cancer: APC loss unleashes Wnt, KRAS mutation drives growth, then TP53 and TGF-beta/SMAD4 loss remove the last brakes, or alternatively mismatch repair fails and mutations pile up. Knowing which route a tumour took decides which drugs work.
Colorectal cancer arises from the colorectal epithelium through accumulated alterations in defined oncogenes and tumour suppressors. KEGG map hsa05210 draws two mechanisms of genomic instability. The chromosomal instability (CIN) route follows the classical adenoma to carcinoma sequence: inactivation of APC (germline in familial adenomatous polyposis) or activating mutation of CTNNB1 stabilises beta-catenin and switches on Wnt target genes (MYC, cyclin D1); activating KRAS mutation, or over-expression of EGFR and its ligands (EGF, TGF-alpha, amphiregulin, epiregulin), drives RAS-ERK and PI3K-AKT signalling; then loss of TP53, of SMAD4 and DCC on chromosome 18q, and of TGF-beta receptor II removes growth arrest and apoptosis. The microsatellite instability (MSI) route follows inactivation of the mismatch repair genes MLH1 (usually by promoter hypermethylation) or MSH2 (germline in Lynch syndrome, HNPCC), with secondary frameshift mutations in genes carrying coding microsatellites such as TGFBR2 and BAX.
Dekker and colleagues, The Lancet, 2019 (doi:10.1016/S0140-6736(19)32319-0) place these routes in the clinic: KRAS, NRAS and BRAF status decides whether anti-EGFR antibodies can be used, MSI status decides whether immune checkpoint inhibitors are appropriate, and the consensus molecular subtypes separate MSI-immune, canonical Wnt, metabolic and mesenchymal TGF-beta-driven tumours.
What drugs do about it: anti-EGFR antibodies (cetuximab, panitumumab) block the receptor layer in RAS wild-type, left-sided tumours; encorafenib plus cetuximab treats BRAF V600E disease; KRAS G12C inhibitors (sotorasib, adagrasib) combined with anti-EGFR treat the G12C subset; pembrolizumab, nivolumab and ipilimumab treat MSI-high tumours; bevacizumab, ramucirumab, regorafenib and fruquintinib block VEGF-driven angiogenesis; HER2-directed therapy (trastuzumab with tucatinib, trastuzumab deruxtecan) treats HER2-amplified tumours. No approved drug yet targets the APC/Wnt step itself.
A car with several independent brakes and an accelerator. APC loss removes the handbrake (Wnt runs), KRAS jams the accelerator, TP53 and SMAD4 loss cut the foot brakes. In the MSI route the mechanic who proofreads the repair manual (mismatch repair) is sacked, so faults accumulate everywhere at once, which oddly makes the car more visible to the immune system's traffic police.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It turned sidedness from an epidemiological curiosity into a mechanistic statement, and it is the reason a wild-type mitogenic report on a left-sided tumour is read as ligand dependence rather than as an absence.
It is the reference description of the disease and the source of the hypermutated split that decides who gets immunotherapy; it also put HER2 on the colorectal map as a drug target.
One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Every screening programme rests on this paper: if cancer arrives through a polyp that takes years to progress, then finding and removing polyps prevents cancer rather than merely catching it early.
Shares APC, TGF-β signalling, Ramucirumab, Mismatch repair & microsatellite instability.
Shares MLH1, Mismatch repair & microsatellite instability, Wnt / β-catenin, PIK3CA / PI3K-alpha.
Shares Panitumumab, Trifluridine/tipiracil, Fruquintinib, Encorafenib.
Shares VEGF angiogenesis, TGF-β signalling, Ramucirumab, Regorafenib.
Shares Comprehensive molecular characterization of human colon and rectal cancer, TGF-β signalling, Early-onset colorectal cancer (under 50), BRAF V600E-mutant colorectal cancer.
Shares Adagrasib, Panitumumab, Tucatinib, Encorafenib.
Shares SMAD4, Adagrasib, TGF-β signalling, Sotorasib.
Shares NRAS, Encorafenib, p53 / RB / cell-cycle checkpoint, PI3K / AKT / mTOR.