Abstract
Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease.
Highlights
Gastrointestinal malignancies rank as the second most death causing condition, with lower incidences than certain other cancers globally [1,2,3]
Gastric cancer is a disease with a high mortality rate with nearly three quarter of a million deaths annually
Methylation of genes forms the basis of most of these epigenetic variations and of other parameters like Microsatellite instability (MSI) which is common in gastric cancer patients
Summary
Gastrointestinal malignancies rank as the second most death causing condition, with lower incidences than certain other cancers globally [1,2,3]. Methylation of the promoter region of this gene as well MMR genes coding for MutS homologues 2, 3, and 6 like MSH2, MSH6, or PMS2 shows decrease in the gene activity and is associated mainly with hereditary non-polyposis colon cancer or Lynch syndrome Some studies on this have show epigenetic inactivation in gastric cancer [49]. Loss of p16 activity by point mutations and homozygous deletions is common in most types of cancer, further studies suggest de novo methylation of the 3’ end promoter region of specific CpG sites surrounding the ATG initiation codon of p16 and hypermethylation of exon 1α coding region as predominant mechanisms of p16 inactivation during tumourigenesis of gastric carcinoma [51]. In gastric cancer apart from the broadly studied DNA methylation of the promoter region of p16, acetylation and dimethylation of Lys-9 residues on H3 contributes to silencing of the tumour suppressor gene [63].
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