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Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

High level of microsatellite instability (MSI-H) in colorectal cancer (CRC) is caused by the inactivation of mismatch repair (MMR) genes; however, it is unknown for tumors with low level MSI (MSI-L). The protein complex involving MSH3 preferentially recognizes insertion/deletion loops (IDLs) of two to eight bases and di- and tetranucleotide repeats are affected in the majority of MSI-L CRC.

Methods

We selected 10 and eight MSI-L CRCs from 228 and 204 patients with sporadic and hereditary disease, respectively. The tumors were analyzed for protein expression of MSH3, MSH2, MSH6, MLH1, and PMS2, and for mutations and loss of heterozygosity (LOH) in MSH3.

Results

Four tumors showed a markedly reduced MSH3 expression, whereas all 18 tumors had normal expression of the remaining MMR proteins. Twenty-five different sequence variants were identified. None of these results in a truncated protein, though L902W represents the first constitutional missense mutation in MSH3 predicted to be functional based on conservation among mutS homologues. All variants have also been found in normal DNA of the patients and in controls. LOH intragenic to MSH3 was evident for 12 of 16 (75%) informative tumors.

Conclusions

Occurrence of sequence variants in normal DNA of the patients and in controls excludes somatic mutations and mutations specific to the CRC patient population, respectively. In contrast, the high frequency of LOH as well as the aberrant protein expression in some tumors indicates an involvement of MSH3 impairment in MSI-L CRC.

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Acknowledgments

We thank Ms. Reichmann and Ms. Colditz for excellent technical assistance. We would like to thank Prof. J. Jiricny and Dr. G. Marra (Institute for Molecular Cancer Research, University of Zurich, Switzerland) for kindly providing the polyclonal MSH3 antibody. This work was supported in part by the Wilhelm Sander Stiftung Grant 2005.062.1 and the Deutsche Forschungsgemeinschaft Grant PL 311/1-1.

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Authors and Affiliations

  1. Department of Surgical Research, Carl Gustav Carus Klinikum, Technical University Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Jens Plaschke, Mark Preußler & Hans K. Schackert

  2. Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany

    Andreas Ziegler

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  1. Jens Plaschke
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  2. Mark Preußler
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Correspondence to Jens Plaschke.

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Plaschke, J., Preußler, M., Ziegler, A. et al. Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability. Int J Colorectal Dis 27, 911–919 (2012). https://doi.org/10.1007/s00384-011-1408-0

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