Molecular genetics of gastric adenocarcinoma in clinical practice

Abstract

The molecular genetics of gastric carcinoma (GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori (H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability (MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene (CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, may provide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mTOR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.

Keywords: Molecular genetics; Lauren classification; Intestinal type gastric cancer; Diffuse type gastric cancer; Molecular Biomarker

Core tip: Intestinal and diffuse cell types of gastric carcinoma have a significant difference in clinical outcome with different molecular pathogenetic pathways. Intestinal type gastric carcinoma (GC) is associated with chromosomal and/or microsatellite instability, mutation of tumor suppressor genes, and loss of heterozygosity. Diffuse type GC is commonly associated with mutation of the E-cadherin gene, and a manifestation of the hereditary gastric cancer syndrome. Detection of certain mutations may aid in early diagnosis, screening, and prognostication of GC, and common genetic alterations may offer therapeutic targets for treatment. Furthermore, potential therapeutic biomarkers for GC are under investigation and may hold future promise.