Patterns of genomic instability in gastric cancer: clinical implications and perspectives

Abstract

In gastric cancer (GC) the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It is widely accepted that GC can follow at least two major genomic instability pathways, microsatellite instability (MSI) and chromosome instability (CIN). MSI is responsible for a well-defined subset of GCs. CIN represents a more common pathway comprising heterogeneous subsets of GC. In addition to MSI and CIN, the CpG islands methylator phenotype (CIMP) plays an important role in gastric carcinogenesis. CIMP may lead to the transcriptional silencing of various genes in gastric carcinogenesis. Intriguingly, more recently in addition to CpG island hypermethylation, a global DNA demethylation, that precedes genomic damage, has been observed in GC. Thus, epigenetic alterations may play a relevant role in gastric carcinogenesis as alternative mechanisms. Evidence suggests that although MSI, CIN and CIMP phenotypes can be distinguished from one another, there might be some degree of overlap. This review describes our current knowledge of the instability pathways in gastric carcinogenesis and the potential clinical applications for different forms of genomic instability in GC.

Clinicopathologic features of gastric cancer with synchronous and metachronous colorectal cancer in Korea: are microsatellite instability and p53 overexpression useful markers for predicting colorectal cancer in gastric cancer patients?

“…There could be two reasons for the lack of a significant association between MSI-H and CRC development in GC. In our study, 7.8 % of GC patients showed MSI-H, which is lower than the corresponding percentages reported in other studies [33]; however, the number of GC patients with MSI-H in the present study was relatively small. Furthermore, the carcinogenic pathways differ for GC and CRC.…”

“…DNA methylation is an agerelated phenomenon and MSI-H sporadic CRCs are more frequent in the elderly [32]. In GC, the frequency of MSI has been reported as 8-37 %, depending on the cases and the number of markers examined [33,34], and some reports indicate that patients with GC with MSI show an increased risk for developing double primary cancer [3,35]. Previous studies on the development of CRC in GC patients did not assess MSI status.…”

Genomic instability and DNA ploidy are linked to DNA copy number aberrations of 8p23 and 22q11.23 in gastric cancers

“…Twelve out of 27 (44.4%) gastric cancers were classified as CIN-positive cancers. The percentage of CIN-positive cancers observed in this series of tumors is consistent with reports by others (5,20,21). Although CIN and aneuploidy are not equivalent, they are interrelated in gastric cancers.…”

Mismatch repair gene expression in gastroesophageal cancers

“…Multiple biological pathways are responsible for DNA repair and have important roles in the maintenance of genome integrity. Genomic instability has been associated with a variety of human cancers, including gastric cancer (4,5).…”

“…The deficiency in the MMR system leads to microsatellite instability and confers a mutator phenotype. This phenomenon has not only been identified in gastric cancer but also in intestinal metaplasia, indicating that it might be present in incipient stages of carcinogenesis (4,11,12). MMR gene variants may influence gene expression, leading to an increased susceptibility to mutations of more genes involved in gastric carcinogenesis (13).…”