Molecular pathology of gastric carcinoma

E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)

Gastric adenocarcinoma develops as a result of an interaction between predisposing environmental conditions, genetic and epigenetic abnormalities, and mutations that affect oncogenes, tumor suppressor genes, and DNA mismatch repair genes [88–90]. The majority of gastric cancers are associated with an infectious etiology, including the Helicobacter pylori [91] and Epstein–Barr virus (EBV) [27]. The distribution of histological subtypes of the disease and the frequencies of H. pylori and EBV associated gastric cancer vary across the world [92]. A minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1) [93] or DNA mismatch repair genes (Lynch syndrome) [94], whereas sporadic mismatch repair-deficient associated gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP) [95].

Table 4.4. Grading system for tumor regression following administration of neoadjuvant therapy [87]

Description Tumor regression grade
No viable cancer cells 0 (Complete response)
Single cells or small groups of cancer cells 1 (Moderate response)
Residual cancer outgrown by fibrosis 2 (Minimal response)
Minimal or no tumor kill; extensive residual cancer 3 (Poor response)

Lauren’s phenotypic classification of gastric cancer into intestinal or diffuse subtypes has been valuable in providing the basis for providing a genotypic classification of gastric carcinoma. Previously, molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing [72, 96–98]. However, these studies have not led to a pathobiology classification scheme of the disease.

Recently, The Cancer Genome Atlas (TCGA) has developed a robust molecular classification of gastric cancer and identified dysregulated pathways and some candidate driver mutations of distinct classes of gastric cancer [29]. The TCGA studies have characterized four major genomic subtypes of gastric cancer: (1) EBV-infected cancer, (2) MSI cancer, (3) genomically stable cancer, and (4) chromosomally unstable cancer. These molecular subtypes reveal prominent genomic features, and provide a guide to targetable agents. This work will facilitate the development of clinical trials to explore therapies in defined sets of patients, ultimately improving survival from this deadly disease [29].

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