Gastric Cancer

Gastric cancer is a major health burden worldwide. It is the second cause of cancer deaths after lung cancer ^{[1] [2]}. Gastric cancer (also known as stomach cancer) is an abnormal growth of cells that begins in the stomach. The stomach, a muscular sac located in the upper middle of your abdomen, which is used to receive and hold the food you eat and then help to break down and digest it.

In order to relate molecular features to histological phenotypes and clinical features, several different molecular gastric cancers classification systems have been proposed in the past decade. In 2014, based on the analysis from The Cancer Genome Atlas (TCGA) research network, four molecularly distinct gastric cancer subtypes were proposed: Epstein-Barr virus-positive (EBV+), microsatellite instable (MSI), genomically stable, and chromosomal unstable (CIN). Among of them, MSI, CIN, and EBV+ had previously been identified as distinct subtypes.

Figure 1. Graphical depiction of overlapping classifications

*this diagram is derived from publication on Lancet ^[3]

The figure 1 shows some overlap with TCGA. In an analysis based on mRNA expression profiling done by the Asian Cancer Research Group, gastric cancers were classified as MSI, microsatellite stable (MSS) or epithelial mesenchymal transition, MSS with TP53 intact, or MSS with TP53 loss. TP53 mutation or overexpression by immunohistochemistry has been proposed as a surrogate for the presence of CIN. Although molecular characteristics (either specific gene alterations or broader molecular subtypes) rather than morphological features might guide future treatment development, Laurén’s classification is still the most commonly used for subgroup analyses in clinical trials.

In this article, we list part of these proteins involved in gastric cancer based on the information provided by NCG (web resource to analyze duplicability, orthology and network properties of cancer genes).

Here, we display several key targets involved in mechanism of gastric cancer, including:

• ARID1A (AT-rich interactive domain-containing protein 1A) is a key component of the SWI/SNF chromatin remodeling complex, which has been reported involved in the carcinogenesis of various organs, including the ovaries, endometrium, uterus, and stomach ^{[4] [5] [6] [7]}. The SWI/SNF complex regulates target genes downstream of TP53. So ARID1A is considered to act as a tumor suppressor gene. Loss of ARID1A expression is correlated with poor prognosis in gastric cancer ^[8].

• CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers ^[9].

• RHOA (ras homolog family member A), a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. RhoA and COX-2 were upregulated in early gastric cancer tissues, which facilitated the proliferation and migration of gastric cancer cells.

• CTNNB1 (beta catenin) is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcription. Mutations in CTNNB1 have been frequently detected (approximately 30%) in intestinal- and diffuse-type gastric carcinomas displaying nuclear accumulation of β-catenin ^[10]. These mutations occur mainly in exon 3, that encodes for the GSK3β phosphorylation consensus region of the β-catenin gene, resulting in mutants refractory to regulation by the destruction complex, and thus in accumulation of this protein and constitutive activation of the Wnt pathway ^[11].