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Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer
Nor Hasyimah Haron1,2, Ezanee Azlina Mohamad Hanif, Mohd Rizal Abdul Manaf
1Department of Pathology, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
Abstract:
Introduction: Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method: A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes. Results: Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All these results however were not statistically significant. Our sequencing data displayed novel mutations. However these data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was comparable with published results. Determination of affected MMR genes by more than two antibodies may increase the sensitivity of IHC to that of MSI analysis.
Insights
Microsatellite instability (MSI) was detected in 16.7% of gastric cancers in Malaysia, with some cases showing MLH1 or MSH2 protein loss. Further research with more antibodies is suggested to improve diagnostic sensitivity.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Microsatellite instability (MSI) is a key indicator of DNA mismatch repair (MMR) gene defects, particularly MLH1 and MSH2.
- MSI is implicated in various cancers, including gastric cancer (GC), but its prevalence in Malaysia was previously unreported.
Purpose of the Study:
- To determine the MSI status in Malaysian gastric cancer cases.
- To investigate the association between MSI, MLH1/MSH2 protein expression, and Helicobacter pylori infection.
- To identify mutations in MLH1 and MSH2 genes in MSI-positive gastric cancers.
Main Methods:
- Microsatellite analysis using a panel of five markers on paired normal and tumor tissues from 60 GC cases.
- Immunohistochemistry (IHC) to assess MLH1 and MSH2 protein expression and H. pylori status.
- DNA sequencing of MSI-positive cases to detect mutations in MLH1 and MSH2 genes.
Main Results:
- Ten (16.7%) gastric cancer cases were identified as MSI-positive.
- Six MSI-positive cases (10.3%) exhibited loss of MLH1 (n=3) or MSH2 (n=3) protein expression via IHC.
- The most common marker in MSI-positive cases was BAT26 (90%); nine cases were intestinal type and located distally. H. pylori was detected in 21.7% of cases.
- Novel mutations were found via sequencing, but not statistically correlated with protein expression, possibly due to small sample size.
Conclusions:
- The observed frequency of MSI in Malaysian gastric cancer is comparable to international findings.
- Immunohistochemistry sensitivity for detecting MMR gene defects may be enhanced by using more than two antibodies.
- Further studies with larger sample sizes are needed to establish statistical significance and explore correlations.
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