# Gastric cancer (KEGG map)

Source: https://onco.cc/pathways/gastric-cancer-signalling/  
OnCo record `gastric-cancer-signalling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-10
- Also known as: KEGG hsa05226; Gastric cancer
- Analogy: 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.
- Interventions: HER2-positive: trastuzumab plus chemotherapy and pembrolizumab first line; trastuzumab deruxtecan or zanidatamab after progression; HER2-negative, PD-L1 expressing: nivolumab or pembrolizumab with chemotherapy; Claudin 18.2-positive: zolbetuximab with chemotherapy; FGFR2b over-expressing: bemarituzumab (phase 3); MET amplified: MET inhibitors in trials; Second line: ramucirumab (VEGFR2) with paclitaxel; MSI-high: checkpoint inhibitors; E-cadherin/CDH1 loss: no direct drug yet

## Sources

- KEGG map hsa05226: https://www.kegg.jp/pathway/hsa05226
- Review: Gastric cancer (Lancet seminar): https://doi.org/10.1016/S0140-6736(20)31288-5

## Connected records

- pathways: [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [FGF / FGFR signalling](https://onco.cc/pathways/fgfr-signalling/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- cancers: [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/)
- targets: [APC](https://onco.cc/targets/apc/), [CDH1](https://onco.cc/targets/cdh1/), [Claudin 18.2](https://onco.cc/targets/cldn18-2/), [FGFR2](https://onco.cc/targets/fgfr2/), [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/), [PD-1](https://onco.cc/targets/pd1/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [TP53](https://onco.cc/targets/tp53/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Bemarituzumab](https://onco.cc/drugs/bemarituzumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Zanidatamab](https://onco.cc/drugs/zanidatamab/), [Zolbetuximab](https://onco.cc/drugs/zolbetuximab/)
- key papers: [Gastric cancer](https://onco.cc/key-papers/paper-smyth-lancet/)

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