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Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation.
Mol Carcinog. 2010 Feb; 49(2):175-82.MC

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.

Authors+Show Affiliations

Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19852062

Citation

Michel, Sara, et al. "Coding Microsatellite Instability Analysis in Microsatellite Unstable Small Intestinal Adenocarcinomas Identifies MARCKS as a Common Target of Inactivation." Molecular Carcinogenesis, vol. 49, no. 2, 2010, pp. 175-82.
Michel S, Kloor M, Singh S, et al. Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation. Mol Carcinog. 2010;49(2):175-82.
Michel, S., Kloor, M., Singh, S., Gdynia, G., Roth, W., von Knebel Doeberitz, M., Schirmacher, P., & Bläker, H. (2010). Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation. Molecular Carcinogenesis, 49(2), 175-82. https://doi.org/10.1002/mc.20587
Michel S, et al. Coding Microsatellite Instability Analysis in Microsatellite Unstable Small Intestinal Adenocarcinomas Identifies MARCKS as a Common Target of Inactivation. Mol Carcinog. 2010;49(2):175-82. PubMed PMID: 19852062.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation. AU - Michel,Sara, AU - Kloor,Matthias, AU - Singh,Sandhya, AU - Gdynia,Georg, AU - Roth,Wilfried, AU - von Knebel Doeberitz,Magnus, AU - Schirmacher,Peter, AU - Bläker,Hendrik, PY - 2009/10/24/entrez PY - 2009/10/24/pubmed PY - 2010/2/19/medline SP - 175 EP - 82 JF - Molecular carcinogenesis JO - Mol Carcinog VL - 49 IS - 2 N2 - 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. SN - 1098-2744 UR - https://www.unboundmedicine.com/medline/citation/19852062/Coding_microsatellite_instability_analysis_in_microsatellite_unstable_small_intestinal_adenocarcinomas_identifies_MARCKS_as_a_common_target_of_inactivation_ L2 - https://doi.org/10.1002/mc.20587 DB - PRIME DP - Unbound Medicine ER -