Molecular pathology

Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.
Matteo Fassan, M.D., Ph.D.

Last author update: 22 June 2020
Last staff update: 6 August 2021

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PubMed Search: Molecular pathology of stomach cancer[TI]

Matteo Fassan, M.D., Ph.D.
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Cite this page: Fassan M. Molecular pathology. website. Accessed September 26th, 2023.
Definition / general
Essential features
The Cancer Genome Atlas (TCGA) network classification
  • EBV positive tumors (~9%)
    • Gastric fundus or body
    • Male prevalence
    • Extensive DNA promoter hypermethylation
    • CDKN2A (p16INK4A) promoter hypermethylation
    • PIK3CA, ARID1A and BCOR mutations
    • Overexpression of PDL1 and PDL2 (assessable with IHC)
  • Tumors with MSI (~22%)
    • Preferred localization in the gastric antrum
    • Associated with intestinal histotype
    • Elderly age of onset
    • More favorable prognosis than the other molecular subtypes
    • MLH1 gene promoter hypermethylation
    • High mutational burden
    • In contrast to MSI colorectal adenocarcinoma, there is no association with BRAF mutations
    • Can be part of the spectrum of inherited malignancies such as Lynch syndrome
  • Genomically stable tumors (~20%)
    • Distal localization
    • Poorly cohesive histotype
    • Younger patients in comparison to other molecular subtypes
    • Worst prognosis among the 4 TCGA subtypes
    • Low copy number alterations
    • Low mutational burden
    • ARID1, RHOA and CDH1 mutations
    • CLDN18-ARHGAP26 fusions in 15%
  • Tumors with chromosomal instability (CIN) (~50%)
    • Frequently located at the gastroesophageal junction / cardia
    • Most are classified as intestinal type
    • DNA aneuploidy and highly variable chromosomal copy numbers
    • Frequent mutations of the tumor suppressor TP53
    • Frequent genomic amplifications of receptor tyrosine kinases (RTKs) / RAS pathway, including epidermal growth factor receptor (EGFR), ERBB2 (HER2), ERBB3, MET proto-oncogene (MET), fibroblast growth factor receptor 2 (FGFR2), vascular endothelial growth factor A (VEGFA) and KRAS
  • Reference: Nature 2014;513:202
The Asian Cancer Research Group (ACRG) classification
  • Microsatellite unstable (MSI) tumors (~23%)
    • Preferred location in the gastric antrum
    • Intestinal histology
    • Often diagnosed at an early stage
    • Best overall prognosis
    • Silencing of MLH1 gene
    • DNA methylation signature
    • Presence of hypermutation
    • Mutations of ARID1A, KRAS and ALK
    • Alterations affecting the PI3K-PTEN-mTOR pathway
    • Overexpression of PDL1 (assessable with IHC)
  • Epithelial to mesenchymal-like type tumors (microsatellite stable [MSS] / EMT) (~15%)
    • Poorly cohesive histotype
    • Younger age at presentation compared to all other subtypes
    • Higher TNM stages at presentation (III / IV)
    • Higher frequency of peritoneal metastases
    • Worst prognosis
    • CDH1 loss of expression
    • Lower number of mutation events when compared to the other MSS groups
  • MSS / TP53 positive tumors (~26%)
    • Intestinal histology
    • Male predominance
    • Frequent EBV infection
    • Frequent mutations in ARID1A, PIK3CA, SMAD4 and APC
  • MSS / TP53 negative tumors (~36%)
    • Intestinal histology
    • Male predominance
    • Highest prevalence of TP53 and RHOA mutations ("TP53 negative" refers to loss of function, not presence of mutation)
    • Mutations in APC, ARID1A, KRAS, PIK3CA and SMAD4
  • Reference: Nat Med 2015;21:449
Clinical features
Prognostic factors
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Matteo Fassan, M.D., Ph.D.

HER2 3+ positive gastric adenocarcinoma

EBER positive gastric adenocarcinoma

MLH1 negative gastric adenocarcinoma

Positive stains
Board review style question #1

What is an important molecular characteristic associated with microsatellite unstable gastric carcinomas?

  1. Frequent amplification of the ERBB2 (HER2) gene
  2. High frequency of BRAF mutations
  3. High mutational burden
  4. Poor prognosis
  5. Poorly cohesive histotype
Board review style answer #1
C. High mutational burden. Alterations in the DNA mismatch repair machinery results in the accumulation of frame shift mutations (either through insertions or deletions) with a subsequent increased mutational burden.

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Reference: Molecular pathology of stomach cancer
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