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Microsatellite instability, Epstein-Barr virus, mutation of type II transforming growth factor beta receptor and BAX
S Y Leung1, S T Yuen, L P Chung
1Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Abstract:
Microsatellite instability (MI), the phenotypic manifestation of mismatch repair failure, is found in a proportion of gastric carcinomas. Little is known of the links between MI and Epstein-Barr virus (EBV) status and clinicopathological elements. Examination of genes mutated through the MI mechanism could also be expected to reveal important information on the carcinogenic pathway. Seventy-nine gastric carcinomas (61 EBV negative, 18 EBV positive) from local Hong Kong Chinese population, an intermediate-incidence area, were examined. Eight microsatellite loci, inclusive of the A10 tract of type II transforming growth factor beta receptor (TbetaR-II), were used to evaluate the MI status. MI in the BAX and insulin-like growth factor II receptor (IGF-IIR) genes were also examined. High-level MI (>40% unstable loci) was detected in ten cases (12.7%) and low-level MI (1-40% unstable loci) in three (3.8%). High-level MI was detected in two EBV-associated cases (11%) and the incidence was similar for the EBV-negative cases (13%). The high-level MIs were significantly associated with intestinal-type tumours (P = 0.03) and a more prominent lymphoid infiltrate (P = 0.04). Similar associations were noted in the EBV-positive carcinomas. The high-level MIs were more commonly located in the antrum, whereas the EBV-associated carcinomas were mostly located in body. Thirteen cardia cases were negative for both high-level MI and EBV. All patients aged below 55 were MI negative (P = 0.049). Of the high-level MIs, 80% had mutation in TbetaR-II, 40% in BAX and 0% in IGF-IIR. Of low-level MIs, 33% also had TbetaR-II mutation. These mutations were absent in the MI-negative cases. Of three lymphoepithelioma-like carcinomas, two cases were EBV positive and MI negative, one case was EBV negative but with high-level MI. In conclusion, high-level MIs were present regardless of the EBV status, and were found in a particular clinicopathological subset of gastric carcinoma patient. Inactivation of important growth regulatory genes observed in these carcinomas confirms the importance of MI in carcinogenesis.
Insights
Microsatellite instability (MI) occurs in gastric cancer regardless of Epstein-Barr virus (EBV) status. High-level MI is linked to intestinal-type tumors and younger patients, impacting growth regulatory genes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability (MI), a result of DNA mismatch repair failure, is observed in some gastric cancers.
- The relationship between MI, Epstein-Barr virus (EBV) status, and clinicopathological features in gastric cancer is not well understood.
- Investigating genes mutated via MI can offer insights into gastric cancer development.
Purpose of the Study:
- To evaluate the prevalence of MI in gastric carcinomas.
- To determine the association between MI, EBV status, and clinicopathological characteristics.
- To identify genes frequently mutated in MI-positive gastric cancers.
Main Methods:
- Seventy-nine gastric carcinomas from Hong Kong Chinese were analyzed for MI status using eight microsatellite loci, including TbetaR-II, BAX, and IGF-IIR.
- EBV status was determined for all cases.
- Clinicopathological data and patient age were correlated with MI and EBV status.
Main Results:
- High-level MI was detected in 12.7% of cases, with similar prevalence in EBV-positive (11%) and EBV-negative (13%) tumors.
- High-level MI was significantly associated with intestinal-type tumors (P=0.03) and prominent lymphoid infiltrate (P=0.04).
- Mutations in TbetaR-II (80%) and BAX (40%) were common in high-level MI cases, while IGF-IIR mutations were absent. Younger patients (<55 years) were MI-negative (P=0.049).
Conclusions:
- High-level MI is present in a distinct subset of gastric carcinomas, irrespective of EBV status.
- MI plays a significant role in gastric carcinogenesis through the inactivation of critical growth regulatory genes.
- The findings highlight the importance of MI in gastric cancer pathogenesis and suggest potential therapeutic targets.