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  • Original Paper
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Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Oncogene volume 19, pages 2249–2256 (2000)Cite this article

Abstract

Inactivation of DNA-mismatch repair underlies the genesis of microsatellite unstable (MSI) colon cancers. hPMS2 is one of several genes encoding components of the DNA-mismatch repair complex, and germline hPMS2 mutations have been found in a few kindreds with hereditary nonpolyposis colorectal carcinoma (HNPCC), in whom hereditary MSI colon cancers develop. However, mice bearing null hPMS2 genes do not develop colon cancers and hPMS2 mutations in sporadic human colon cancers have not been described. Here we report that in Vaco481 colon cancer the hPMS2 gene is inactivated by somatic mutations of both hPMS2 alleles. The cell line derived from this tumor is functionally deficient in DNA mismatch repair. This deficiency can be biochemically complemented by addition of a purified hMLH1-hPMS2 (hMutLα) complex. The hPMS2 deficient Vaco481 cancer cell line demonstrates microsatellite instability, an elevated HPRT gene mutation rate, and resistance to the cytotoxicity of the alkylator MNNG. We conclude that somatic inactivation of hPMS2 can play a role in development of sporadic MSI colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mismatch repair system.

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Abbreviations

AGT:

O6-Alkylguanine DNA Alkyltransferase

CE:

Cloning Efficiency

H6:

A subclone of HCT116

HNPCC:

Hereditary NonPolyposis Colorectal Carcinoma

I/D:

Insertion/Deletion

MSI:

Microsatellite Instability

O6BG:

O6-benzylguanine

PCR:

Polymerase Chain Reaction

6TG:

6-Thioguanine

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Acknowledgements

The authors would like to thank Dr JKV Willson for helpful discussion and for establishing the Vaco481 cell line. We thank Richard Boland for providing the HCT116 and HCT116-CR3 cell lines, and we thank Dan Robinson, Lois Myeroff, Petra VanDerMark, Lili Liu and Stan Gerson for helpful discussions. This work was supported by NIH grants RO1 CA67409 (to SD Markowitz), RO1 CA 70788 (to ML Veigl), RO1 GM45190 (to P Modrich), KO8 CA 71554 (to SJ Littman) and by grant #96B084 (to WD Sedwick) from the American Institute for Cancer Research. SD Markowitz and P Modrich are Investigators of the Howard Hughes Medical Institute.

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Author notes

  1. Martina L Veigl, Sanford D Markowitz and W David Sedwick: ML Veigl, SD Markowitz and WD Sedwick contributed equally to this study

Authors and Affiliations

  1. Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, 44106, Ohio, OH, USA

    Ai-Hong Ma, Sandra Swinler, Joseph Olechnowicz, Martina L Veigl, Sanford D Markowitz & W David Sedwick

  2. Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, 44106, Ohio, OH, USA

    Sandra Swinler, Gabriel Lader, Alexander Polinkovsky, Sanford D Markowitz & W David Sedwick

  3. Howard Hughes Medical Institute, Suite 200, 11001 Cedar Road, Cleveland, 44106, Ohio, OH, USA

    Lakshmi Kasturi, James Lutterbaugh & Sanford D Markowitz

  4. Department of Environmental Health Sciences, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, 44106, Ohio, OH, USA

    Ai-Hong Ma

  5. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, 44106, Ohio, OH, USA

    Liang Xia

  6. Howard Hughes Medical Institute, Duke University Medical Center, Nanaline Duke Building, Durham, 27710, North Carolina, NC, USA

    Paul Modrich

  7. Department of Medicine, Duke University, Durham, 27710, North Carolina, NC, USA

    Susan J Littman

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  1. Ai-Hong Ma
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Ma, AH., Xia, L., Littman, S. et al. Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability. Oncogene 19, 2249–2256 (2000). https://doi.org/10.1038/sj.onc.1203568

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