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This KEGG map splits stomach cancer into two routes: the intestinal type that accumulates TP53, APC and HER2 changes step by step, and the diffuse type driven by loss of the cell glue E-cadherin plus MET or FGFR2 amplification. It matters because HER2, FGFR2, claudin 18.2 and PD-1 status now decide first-line treatment.
Gastric cancer is one of the most common cancers worldwide and is divided by the Lauren classification into intestinal and diffuse types. KEGG map hsa05226 draws the intestinal-type sequence: intestinal metaplasia carries TP53 mutation, reduced retinoic acid receptor beta and hTERT expression; gastric adenomas add APC mutation, reduced p27 (CDKN1B) and cyclin E amplification; advanced tumours show ERBB2 (HER2) amplification, reduced TGF-beta receptor I and complete loss of p27. Amplified HER2, FGFR2 and MET all feed RAS-ERK and PI3K-AKT; CDX2 over-expression alters transcription. The diffuse type is defined by loss of E-cadherin through CDH1 mutation (germline in hereditary diffuse gastric cancer), which releases beta-catenin, and by MET and FGFR2 amplification.
Smyth and colleagues, The Lancet, 2020 (doi:10.1016/S0140-6736(20)31288-5) review the disease: Helicobacter pylori is the main cause, The Cancer Genome Atlas separates EBV-positive, MSI, genomically stable (diffuse, CDH1 and RHOA altered) and chromosomally unstable (intestinal, receptor amplified) subtypes, and biomarker testing for HER2, PD-L1 and MSI guides therapy.
What drugs do about it: trastuzumab plus chemotherapy, now with pembrolizumab, is standard for HER2-positive disease, with trastuzumab deruxtecan and zanidatamab after progression; nivolumab or pembrolizumab with chemotherapy treats HER2-negative disease with PD-L1 expression; zolbetuximab treats claudin 18.2-positive tumours; ramucirumab blocks VEGFR2 in second line; the FGFR2b antibody bemarituzumab is in phase 3 for FGFR2b over-expressing tumours; MSI-high tumours respond to checkpoint inhibitors. The CDH1/E-cadherin loss that defines diffuse cancer has no direct drug.
Two different ways a wall fails. In the intestinal type the bricks are replaced one at a time with faulty ones (TP53, APC, HER2) until the wall bows outward. In the diffuse type the mortar (E-cadherin) dissolves, so the bricks scatter and slip between other layers. The drugs mostly aim at loudspeakers bolted to the wall (HER2, FGFR2, claudin 18.2) rather than the bricks or mortar.
Shares Mismatch repair & microsatellite instability, Wnt / β-catenin, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint.
Shares APC, TGF-β signalling, Ramucirumab, Mismatch repair & microsatellite instability.
Shares FGF / FGFR signalling, Ramucirumab, Epithelial-mesenchymal transition & drug efflux, FGFR2.
Shares TGF-β signalling, Ramucirumab, Wnt / β-catenin, MET.
Shares Zolbetuximab, Zanidatamab, Claudin 18.2, HER2.
Shares FGF / FGFR signalling, Epithelial-mesenchymal transition & drug efflux, p53 / RB / cell-cycle checkpoint, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares Wnt / β-catenin, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint, PI3K / AKT / mTOR.
Shares Zolbetuximab, Zanidatamab, Claudin 18.2, HER2.