Tumor Microsatellite Instability in Early Onset Gastric Cancer

Abstract

Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. Genetic factors are implicated, including DNA mismatch repair (MMR) deficiency manifested as tumor microsatellite instability (MSI). However, a standardized panel of markers and a definition of low-versus-high level MSI in GC are lacking. We examined a population-based cohort of early onset (<or=50 yrs) gastric cancer. We identified 211 cases of early onset gastric cancer in Central-East Ontario from 1989 to 1993, with archival material available for 139 cases. Testing included a six-mononucleotide marker panel and a three-MMR immunohistochemical panel. Overall, 30% (41 of 139) of GC were MSI+, with allelic shifts at one to eight markers. An unexpected discordance between the BAT-25, BAT-26, and BAT-40 markers was observed in the MSI+ cases. Six cases showing multiple loci instability (>or=3 markers MSI+/MSI-high) demonstrated MMR protein deficiency. Three novel hMLH1 mutations (two germline frameshift and one somatic nonsense) were also found. The only significant clinicopathological associations were increased tumor size in MSI+ cases (P=0.04) and Lauren histotype (P=0.006) and tumor grade (P=0.007) in MSI-high cases. Tumor size, location, depth, nodal status, and Ming subtype were significant prognostic variables. Therefore, we propose a new definition of high-level MSI based on unifying characteristics of instability of more than or equal to three of six mononucleotide markers and loss of MMR protein expression.

Assessment of the beneficial loci and prognostic implications of microsatellite instability in gastric carcinoma

“…In previous reports (2,4,8,19), GC with MSI-H had a significantly higher frequency in older patients and women, and in antrally located and PD tumors, but a low incidence in patients with lymph node (LN) metastasis in comparison with MSI-L or MSS cases. In the current analysis, although not significant, MSI-H was somewhat more frequent in older patients, and was mainly found in the antrum and AGC patients, and exhibited a trend toward a more favorable prognosis in PD tumors.…”

“…Genetic instability in GC represents a key molecular step that occurs early in the carcinogenesis process (2,3). Although numerous studies have been performed to evaluate the genetic events associated with the development and progression of GC (4,5), its molecular mechanism still remains to be understood, and identification of the predictive markers is crucial.…”

“…Previous studies (2)(3)(4)(5) have revealed that colorectal cancers exhibit distinctive clinicopathological characteristics and prognoses according to the MSI status. However, there is a wide variation in results between MSI status and clinicopathological parameters in GCs due to a lack of standardized and comparable parameters (7).…”

Mismatch repair gene expression in gastroesophageal cancers

“…As a consequence, mismatch mutations accumulate throughout the genome but are particularly concentrated in regions with short repetitive nucleotide sequences known as microsatellites (9)(10)(11). The deficiency in the MMR system leads to microsatellite instability and confers a mutator phenotype.…”

“…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).…”