This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Plaschke, J. Articles by Schackert, H. K. Search for Related Content PubMed PubMed Citation Articles by Plaschke, J. Articles by Schackert, H. K.

Loss of MSH3 Protein Expression Is Frequent in MLH1-Deficient Colorectal Cancer and Is Associated with Disease Progression¹

Department of ¹ Surgical Research, ² Institute of Pathology, ³ Institute of Clinical Genetics, and ⁴ Department of Visceral, Thoracic and Vascular Surgery, Carl Gustav Carus Hospital, Dresden University of Technology, Dresden, Germany, and ⁵ Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

Mononucleotide repeat sequences are particularly prone to frameshift mutations in tumors with biallelic inactivation of the mismatch repair (MMR) genes MLH1 or MSH2. In these tumors, several genes harboring mononucleotide repeats in their coding region have been proposed as targets involved in tumor progression, among which are also the MMR genes MSH3 and MSH6. We have analyzed the expression of the MSH3 and MSH6 proteins by immunohistochemistry in 31 colorectal carcinomas in which MLH1 was inactivated. Loss of MSH3 expression was identified in 15 tumors (48.5%), whereas all tumors expressed MSH6. Frameshift mutations at coding microsatellites were more frequent in MSH3 (16 of 31) than in MSH6 (3 of 31; Fisher’s exact test, P < 0.001). Frameshift mutations and allelic losses of MSH3 were more frequent in MSH3-negative tumors compared with those with normal expression (22 mutations in 30 alleles versus 8 mutations in 28 alleles; ², P = 0.001). Biallelic inactivation was evident or inferred for 60% of MSH3-negative tumors but none of the tumors with normal MSH3 expression. In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2. As it has been suggested that mutations of MSH3 might play a role in tumor progression, we studied the association between MSH3 expression and disease stage assessed by lymph node and distant metastases status. Dukes stages C and D were more frequent in primary tumors with loss of MSH3 expression (9 of 13), compared with tumors with retained expression (1 of 14; Fisher’s exact test, P = 0.001), suggesting that MSH3 abrogation may be a predictor of metastatic disease or even favor tumor cell spread in MLH1-deficient colorectal cancers.

This article has been cited by other articles:

				A. C. Haugen, A. Goel, K. Yamada, G. Marra, T.-P. Nguyen, T. Nagasaka, S. Kanazawa, J. Koike, Y. Kikuchi, X. Zhong, et al. Genetic Instability Caused by Loss of MutS Homologue 3 in Human Colorectal Cancer Cancer Res., October 15, 2008; 68(20): 8465 - 8472. [Abstract] [Full Text] [PDF]

				C. H. Busold, S. Winter, N. Hauser, A. Bauer, J. Dippon, J. D. Hoheisel, and K. Fellenberg Integration of GO annotations in Correspondence Analysis: facilitating the interpretation of microarray data Bioinformatics, May 15, 2005; 21(10): 2424 - 2429. [Abstract] [Full Text] [PDF]

				B Perez-Ordonez, N N Huynh, K W Berean, and R C K Jordan Expression of mismatch repair proteins, {beta} catenin, and E cadherin in intestinal-type sinonasal adenocarcinoma J. Clin. Pathol., October 1, 2004; 57(10): 1080 - 1083. [Abstract] [Full Text] [PDF]