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Published on: July 28, 2010
Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies
Sara Michel1, Matthias Kloor, Sandhya Singh
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
Abstract:
Approximately 15% of small intestinal adenocarcinomas show inactivation of DNA-mismatch repair (MMR) and display high-level microsatellite instability (MSI-H). MSI-H tumors progress as a result of mutations affecting coding microsatellites (coding microsatellite instability, cMSI) that may result in a functional inactivation of the encoded proteins and provide a selective growth advantage for the affected cell. To investigate the cMSI selection in small intestinal carcinogenesis 56 adenocarcinomas were tested for MSI. Eleven MSI-H carcinomas (19.6%) were identified and subjected to cMSI analysis in 24 potentially tumor relevant genes. Mutation frequencies were similar to those observed in colorectal cancer (CRC). Beside high frequencies of cMSI in TGFbetaR2, ACVR2, and AIM2 we detected MARCKS mutations in 10 out of 11 (91%) tumors with a 30% share of biallelic mutations. Since little is known about MARCKS expression in the intestine, we analyzed MARCKS protein expression in 31 carcinomas. In non-neoplastic mucosa, MARCKS was found to be expressed with a concentration gradient along the crypt-villus axis. In line with cMSI induced functional inactivation of MARCKS, 8 out of 11 MSI-H adenocarcinomas showed regional or complete loss of the protein. In microsatellite stable (MSS) small bowel adenocarcinoma, loss of MARCKS expression was seen in 2 out of 20 tumors (10%). In conclusion, we herein present a cMSI profile of MSI-H small intestinal adenocarcinomas identifying MARCKS as a frequent target of mutation. Loss of MARCKS protein expression suggests a significant role of MARCKS inactivation in the pathogenesis of small intestinal adenocarcinomas.
Insights
High microsatellite instability (MSI-H) in small intestinal cancers frequently involves mutations in coding microsatellites (cMSI). This study identifies MARCKS as a common mutation target, with its loss potentially driving small bowel tumor development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Approximately 15% of small intestinal adenocarcinomas exhibit DNA-mismatch repair (MMR) deficiency, leading to high-level microsatellite instability (MSI-H).
- MSI-H tumors accumulate mutations in coding microsatellites (cMSI), potentially causing protein inactivation and conferring a growth advantage.
Purpose of the Study:
- To investigate the role of cMSI in small intestinal carcinogenesis.
- To identify frequently mutated genes and assess the expression of MARCKS in MSI-H small intestinal adenocarcinomas.
Main Methods:
- Tested 56 small intestinal adenocarcinomas for MSI status.
- Performed cMSI analysis on 24 tumor-relevant genes in 11 MSI-H and 20 microsatellite-stable (MSS) tumors.
- Analyzed MARCKS protein expression in 31 carcinomas.
Main Results:
- Identified 11 MSI-H carcinomas (19.6%) and found mutation frequencies comparable to colorectal cancer.
- Detected high frequencies of cMSI in TGFbetaR2, ACVR2, and AIM2, with MARCKS mutations in 91% of MSI-H tumors (30% biallelic).
- Observed reduced MARCKS protein expression in 8/11 MSI-H tumors, correlating with cMSI-induced inactivation, while 10% of MSS tumors also showed loss.
Conclusions:
- Established a cMSI profile for MSI-H small intestinal adenocarcinomas.
- Identified MARCKS as a frequently mutated gene in this context.
- Inactivation of MARCKS protein appears to play a significant role in the pathogenesis of small intestinal adenocarcinomas.
