| Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access |
| Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc |
| Journal website http://www.gastrores.org |
Review
Volume 12, Number 6, December 2019, pages 275-282
Molecular Classification of Gastric Adenocarcinoma
Tables
| G-INT GC | G-DIF GC | |
|---|---|---|
| G-INT: genomic intestinal; G-DIF: genomic diffuse; GC: gastric cancer; AURKB: aurora kinase B; CDH17: cadherin 17; ELOVL5: ELOVL family member 5; FUT2: fucosyltransferase 2; LGALS4: lectin; 5-FU: 5-fluorouracil. | ||
| Histology | Intestinal histology (91/133) | Diffuse histology (64/107) |
| Molecular alterations | Genes up-regulated were related to carbohydrate and protein metabolism (FUT2) and cell adhesion (LGALS4, CDH17) | Cell proliferation (AURKB) and fatty acid metabolism (ELOVL5) functional annotations were enriched |
| Treatment reaction | In vitro study, G-INT cell lines were sensitive to 5-FU and oxaliplatin | In vitro study, G-DIF cell lines were more sensitive to cisplatin |
| Patients with G-INT tumors may derive benefit from adjuvant 5-FU-based therapy | ||
| Prognosis | Superior overall survival | Poor |
| Proliferative GC | Metabolic GC | Mesenchymal GC | |
|---|---|---|---|
| GC: gastric cancer; KEGG: Kyoto Encyclopedia of Genes and Genomes; GO: gene ontology; PI3K/Akt/mTOR: phosphatidylinositol 3-kinase-AKT-mTOR; DNA: deoxyribonucleic acid. | |||
| Histology | Intestinal (73.6%) | Intestinal (53.6%) | Diffuse (58.2%) |
| Molecular alterations | Characterized by gene sets related to the cell cycle: KEGG cell cycle, KEGG DNA replication, and 13 GO gene sets | Characterized by gene sets from several KEGG metabolism pathways and GO digestion | Over-represents the following gene sets: KEGG focal adhesion, KEGG extracellular-matrix–receptor interaction, and GO cell adhesion |
| High number of TP53 mutations | Low TP53 mutations | Low TP53 mutations | |
| Druggable targets | The PI3K-AKT-mTOR pathway could be an effective drug target | ||
| Treatment reaction | More sensitive to 5-fluorouracil treatment | The cell lines of this subtype were particularly sensitive to compounds targeting the PI3K/AKT/mTOR inhibitors in vitro study | |
| Prognosis | Shorter disease-free survival | ||
| Subtypes | EBV-positive | MSI | GS | CIN |
|---|---|---|---|---|
| ARID1A: AT-rich interactive domain-containing protein 1A; BCOR: B-cell lymphoma 6 corepressor; CIN: chromosomal instability; GS: genomically stable; GC: gastric cancer; CIMP: CpG island methylator phenotype; DNMT3b: DNA methyltransferase 3b; EBV: Epstein-Barr virus; EGFR: epithelial growth factor receptor; ERBB2: Erb-B2 receptor tyrosine kinase 2; JAK2: Janus-associated kinase 2; LMP2A: latent membrane protein 2A; LELC: lymphoepithelioma-like carcinoma; MSI: microsatellite instability; PI3K: phosphatidylinositol-3-kinase; RHOA: Ras homolog family member A; TCGA: The Cancer Genome Atlas; PD-L1/2: programmed death ligand-1/2; CDK6: cell division protein kinase 6. | ||||
| Frequency | 8.8% | 21.7% | 19.7% | 49.8% |
| Demographic | Male patients (81%) | Old age (median 72 years) | Young age (median 59 years) | No special |
| Histology | Diffuse histology | Intestinal histology | ||
| Main location | Fundus or body (62%) | Gastro-esophageal junction/cardia (65%) | ||
| Molecular alterations | EBV-CpG island methylator phenotype (CIMP) | Gastric-CIMP | CDH1, RHOA mutation | TP53 mutation |
| PD-L1/2, JAK2 overexpression | Hypermutation in TP53, PIK3CA, ERBB3, ARID1A | CLDN18-ARHGAP fusion | RTK-RAS activation | |
| Mutation in PIK3CA, ARID1A, BCOR | MLH1 silencing | Cell adhesion, angiogenesis pathways enriched | Mutations of SMAD4 and APC | |
| CDKN2A silencing | Mitotic pathways activation | Rare TP53 mutations | ||
| Immune cell signaling | Commune changes in the genes of CMHI | |||
| Rare TP53 mutations | ||||
| Potential targets | PIK3CA, JAK2, PD-L1/PD-L2 | PIK3CA, ERBB2/3, EGFR, PD-L1, MLH1 silencing | RHOA, CLDN18 | RTKs, EGFR, VEGFA, CCNE1, CCND1, CDK6 |
| Treatment reaction | No respond to adjuvant chemotherapy | |||
| Subtypes | MSI GC | MSS/EMT GC | MSS/TP53- GC | MSS/TP53+ GC |
|---|---|---|---|---|
| ACRG: Asian Cancer Research Group; ARID1A: AT-rich interactive domain-containing protein 1A; CDH1: E-cadherin; GC: gastric cancer; MSS/EMT: microsatellite stable/epithelial-mesenchymal transition; MSS/TP53+: microsatellite stable/epithelial/TP53 intact; MSS/TP53-: microsatellite stable/epithelial/TP53 loss; MSI: microsatellite instability; PI3K: phosphatidylinositol-3-kinase; RHOA: Ras homolog family member A; PD-L1: programmed death ligand-1. | ||||
| Frequency | 22.7% | 15.3% | 35.7% | 26.3% |
| Demographic | Diagnosed at a significantly younger age | Male | Male | |
| Histology | Intestinal histology (> 60%) | Diffuse histology (> 80%) | Intestinal histology | Intestinal histology |
| Molecular alterations | Silencing of MLH1 gene | Loss of CDH1 | Highest prevalence of TP53 and RHOA mutations | Frequent EBV infection |
| Mutations in ARID1A, MTOR, KRAS, PIK3CA, ALK, PTEN | Loss of cellular adhesion, angiogenesis, motility | APC, ARID1A, KRAS, PIK3CA, SMAD4 enriched | Frequent mutations in ARID1A, PIK3CA, SMAD4, APC | |
| Overexpression of PD-L1 | ||||
| T cell infiltrate | ||||
| Prognosis | Best overall prognosis, lowest recurrence rate (22%) | Worst prognosis, highest recurrence rate | Intermediate | Intermediate |