Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation

• Verfasst von: Michel, Sara [VerfasserIn]
• Verfasst von: Kloor, Matthias [VerfasserIn]
• Verfasst von: Singh, Sandhya [VerfasserIn]
• Verfasst von: Gdynia, Georg [VerfasserIn]
• Verfasst von: Roth, Wilfried [VerfasserIn]
• Verfasst von: Knebel Doeberitz, Magnus von [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Verfasst von: Bläker, Hendrik [VerfasserIn]
• Titel: Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation
• Verf.angabe: Sara Michel, Matthias Kloor, Sandhya Singh, Georg Gdynia, Wilfried Roth, Magnus von Knebel Doeberitz, Peter Schirmacher, and Hendrik Bläker
• Jahr: 2010
• Umfang: 8 S.
• Fussnoten: Erstmals am 22. Oktober 2009 online veröffentlicht ; Gesehen am 21.04.2023
• Titel Quelle: Enthalten in: Molecular carcinogenesis
• Ort Quelle: New York, NY : Wiley Interscience, 1988
• Jahr Quelle: 2010
• Band/Heft Quelle: 49(2010), 2 vom: Feb., Seite 175-182
• ISSN Quelle: 1098-2744
• DOI: doi:10.1002/mc.20587
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: coding microsatellites
• Sach-SW: DNA-mismatch repair
• Sach-SW: MARCKS
• Sach-SW: microsatellite instability
• Sach-SW: small intestinal carcinoma
• K10plus-PPN: 1843355744

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 TGFβR2, 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. © 2009 Wiley-Liss, Inc.