. 2022 Oct 8;7:358. doi: 10.1038/s41392-022-01190-w

Table 1.

Molecular characterizations and clinical implications of gastric cancer subtypes by TCGA and ACRG classifications

TCGA classification
Molecular characterizations	• High mutation rates and hypermethylation • Gene mutations of kinases: EGFR, HER2/3, JAK2, FGFR2, MET, PIK3CA • Expression loss of HLA class I complex and reduced antigen presentation to the immune system	• Alterations in cell adhesion-related genes: CDH1, RHOA, CLDN18-ARHGAP26 fusion • Upregulated angiogenesis-related pathways	• Frequent DNA hypermethylation • CDKN2A silencing • Mutations in PIK3CA, ARID1A, BCOR, TP53 genes • Amplification of JAK2 and PD-L1/2 • Immune cell signaling enrichment	• Frequent TP53 mutation • Gene amplification of receptor tyrosine kinases: EGFR, HER2/3, JAK2, FGFR2, MET, PIK3CA, NRAS/KRAS
Clinical implications	• Intermediate prognosis • Less sensitive to adjuvant chemotherapy • Sensitive to checkpoint inhibitor immunotherapy	• Poor prognosis • Less sensitive to adjuvant chemotherapy	• Good prognosis • Sensitive to checkpoint inhibitor immunotherapy	• Intermediate prognosis • Sensitive to adjuvant chemotherapy

TCGA classification

Subtypes

MSI (21.7%)

GS (19.7%)

EBV⁺ (8.8%)

CIN (49.8%)

Molecular characterizations

• High mutation rates and hypermethylation

• Gene mutations of kinases: EGFR, HER2/3, JAK2, FGFR2, MET, PIK3CA

• Expression loss of HLA class I complex and reduced antigen presentation to the immune system

• Alterations in cell adhesion-related genes: CDH1, RHOA, CLDN18-ARHGAP26 fusion

• Upregulated angiogenesis-related pathways

• Frequent DNA hypermethylation

• CDKN2A silencing

• Mutations in PIK3CA, ARID1A, BCOR, TP53 genes

• Amplification of JAK2 and PD-L1/2

• Immune cell signaling enrichment

• Frequent TP53 mutation

• Gene amplification of receptor tyrosine kinases: EGFR, HER2/3, JAK2, FGFR2, MET, PIK3CA, NRAS/KRAS

Clinical implications

• Intermediate prognosis

• Less sensitive to adjuvant chemotherapy

• Sensitive to checkpoint inhibitor immunotherapy

• Poor prognosis

• Less sensitive to adjuvant chemotherapy

• Good prognosis

• Sensitive to checkpoint inhibitor immunotherapy

• Intermediate prognosis

• Sensitive to adjuvant chemotherapy

ACRG classification
Molecular characterizations	• High mutation rates in KRAS, ALK, ARID1A, PI3K pathway • Frequent DNA hypermethylation • Loss of MLH1	• Low mutation rates • Loss of CDH1	• EBV positivity • Frequent mutations in APC, ARID1A, KRAS, PIK3CA, SMAD4	• Mutation or loss of TP53 • Gene amplifications of tyrosine kinase receptors like HER2, EGFR, and cell cycle regulators like CCNE1, CCND1, MDM2
Clinical implications	• Mostly diagnosed at early stages (I/II) • Good prognosis and lower frequency of recurrence	• Prevalent in the younger population • Diagnosis at advanced stages (III/IV) • Poor prognosis and high frequency of recurrence	• Intermediate prognosis and chance of recurrence	• Intermediate prognosis and chance of recurrence • High frequency of lymphovascular invasion

ACRG classification

subtypes

MSI (23%)

MSS/EMT (15%)

MSS/TP53⁺ (26%)

MSS/TP53^- (36%)

Molecular characterizations

• High mutation rates in KRAS, ALK, ARID1A, PI3K pathway

• Frequent DNA hypermethylation

• Loss of MLH1

• Low mutation rates

• Loss of CDH1

• EBV positivity

• Frequent mutations in APC, ARID1A, KRAS, PIK3CA, SMAD4

• Mutation or loss of TP53

• Gene amplifications of tyrosine kinase receptors like HER2, EGFR, and cell cycle regulators like CCNE1, CCND1, MDM2

Clinical implications

• Mostly diagnosed at early stages (I/II)

• Good prognosis and lower frequency of recurrence

• Prevalent in the younger population

• Diagnosis at advanced stages (III/IV)

• Poor prognosis and high frequency of recurrence

• Intermediate prognosis and chance of recurrence

• High frequency of lymphovascular invasion

TCGA The Cancer Genome Atlas, ACRG Asian Cancer Research Group, MSI microsatellite instable, EBV Epstein–Barr virus, GS genomically stable, CIN chromosomal unstable, MSS microsatellite stable, EMT epithelial-mesenchymal transition, TP53 tumor protein p53, EGFR epidermal growth factor receptor, HER2/3 human epidermal growth factor receptor 2/3, JAK2 Janus kinase 2, FGFR2 fibroblast growth factor receptor 2, MET mesenchymal-epithelial transition factor, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, HLA human leukocyte antigen, CDKN2A cyclin-dependent kinase inhibitor 2A, ARID1A AT-rich interactive domain-containing protein 1A, BCOR B-cell lymphoma 6 corepressor, PD-L1/2 programmed death-ligand 1/2, CDH1 - cadherin 1, RHOA Ras homolog family member A, CLDN18 Claudin 18, ARHGAP26 Rho GTPase Activating Protein 26, NRAS neuroblastoma RAS viral oncogene homolog, KRAS Kirsten rat sarcoma viral oncogene homolog, ALK anaplastic lymphoma kinase, PI3K phosphoinositide 3-kinase, MLH1 MutL Homolog 1, APC adenomatous polyposis coli, SMAD4 mothers against decapentaplegic homolog 4, CCNE1 & CCND1 cyclin E1 & D1, MDM2 Mouse double minute 2 homolog