Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma

Table 1 Existing molecular classification systems of gastrointestinal tract tumors

Subdividing and data level	Subtype	Prevalence	Defining characteristics
Esophagus subtypes
Liu et al[34] obtained subtypes based on SCNAs, WES, DNA methylation, mRNAseq, microRNAseq, RPPA (TCGA)	EA-CIN	14.1	EA similarity with CIN phenotype of GC. Methylation patterns and gene alterations differ in terms of localization
Guo et al[13] determined differences in expression profiles and somatic mutation profiles by using RNA-Seq and exome-Seq data	EA I	40	EA I shares the common expression profiles with GC
	EA II	60	EA II was clustered with esophageal squamous cell carcinomas
Jammula et al[17] divided OAC and Barrett’s esophagus by integration of WGS and RNA-seq data	Subtype I	28.7	SI: CIMP-like
	Subtype II	27.3	SII: Expression of gene patterns associated with metabolic processes
	Subtype III	22.7	SIII: Immune cell infiltration
	Subtype IV	21.1	SIV: DNA hypomethylation; structural aberrations; CNA
Secrier et al[8] received GC subtypes on the basis of mutation signatures obtained from WGS data	DDR-impaired	15	DDR: Enrichment for BRCA signature with prevalent defects in the homologous recombination pathway
	C > A/T dominant	32	C > A/T: Aging imprint
	Mutagenic	53	Mutagenic: The highest mutational load and the highest load of neoantigens
Gastric subtypes
Tan et al[32] obtained subtypes based on gene expression pattern (microarray)	G-INT	58	G-INT: Genes upregulated were related to carbohydrate and protein metabolism (FUT2) and cell adhesion (LGALS4; CDH17)
	G-DIF	42	G-DIF: Cell proliferation (AURKB) and fatty acid metabolism (ELOVL5) functional annotations were enriched
Lei et al[33] compared the patterns of gene expression samples of GC (mRNA, CNAs)	Proliferative	45	Proliferative: High levels of genomic instability; TP53 mutations and DNA hypomethylation
	Metabolic	23	Metabolic: High expression of genes associated with metabolism
	Mesenchymal	31	Mesenchymal: Contain cells with features of cancer stem cells
TCGA obtained subtypes based on SCNAs, WES, DNA methylation, mRNAseq, microRNAseq, RPPA[12]	EBV+	8.8	EBV: Recurrent mutation of PIK3CA; intense hypermethylation; JAK2, CD274, PDCD1LG2 amplification
	MSI	21.7	MSI: Increased frequency of mutations; aberrant epigenetic patterns
	CIN	49.8	CIN: The presence of multiple chromosomal rearrangements; localization mainly in the proximal gastric cancer and EGJ
	GS	19.7	GS: RHOA, CDH1 and ARID1A mutations; CLDN18-ARHGAP6 gene fusion
Cristescu et al[55] received GC subtypes based on data of gene expression	MSI-high GC	22.7	MSI-high GC: Mutations in ARID1A, MTOR, KRAS, PIK3CA, ALK, and PTEN. Overexpression of PD-L1; T cell infiltrate
	MSS/EMT GC	15.3	MSS/EMT GC: Loss of CDH1; Loss of cellular adhesion, angiogenesis, motility
	MSS/TP53- GC	35.7	MSS/TP53- GC: Highest prevalence of TP53 and RHOA mutations; APC, ARID1A, KRAS, PIK3CA, and SMAD4 enriched
	MSS/TP53+ GC	26.3	MSS/TP53+ GC: Frequent EBV infection; Frequent mutations in ARID1A, PIK3CA, SMAD4, APC
Colon subtypes
Guinney et al[59] carried out combined molecular genetic analysis of 4151 colon tumor samples from 6 different scientific groups	CMS1	14	CMS1: Hypermutated; microsatellite unstable; strong immune activation
	CMS2	37	CMS2: Epithelial, chromosomally unstable; marked WNT and MYC signaling activation
	CMS3	13	CMS3: Epithelial; evident metabolic dysregulation
	CMS4	23	CMS4: Prominent transforming growth factor β activation; stromal invasion and angiogenesis
Liu et al[34] obtained subtypes based on SCNAs, WES, DNA methylation, mRNAseq, microRNAseq, RPPA (TCGA)	MSI	17.5	MSI: MSI tumors with MLH1 methylation were associated with BRAFV600E mutation
	HM-SNV	1.7	HM-SNV: Hotspot mutations in polymerase E
	CIN	66.6	CIMP status is characteristic of CRC with associated mutations in KRAS and TGFβ pathways
	GS	14	GS: Lacking hypermutation and aneuploidy; enriched in DNA hypermethylation and mutations in KRAS, SOX9 and PCBP1

CIMP: CpG island methylator phenotype; CIN: Chromosomally instable; CRC: Colorectal cancer; DDR: DNA damage repair; EA: Esophagus; EBV: Epstein-Barr virus; EGJ: Epigastric junction; GC: Gastric cancer; G-DIF: Gastric diffuse subtype; G-INT: Gastric intestinal subtype; GS: Stable genome; HM-SNV: Hypermutated-single nucleotide variant; MSI: Microsatellite instability; MSS: Microsatellite stability; TCGA: The Cancer Genome Atlas; WGS: Whole genome sequencing.