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Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair

Nature Genetics volume 14, pages 102–105 (1996)Cite this article

Abstract

Many human tumours have length alterations in repetitive sequence elements1. Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds2,3, many sporadic tumours exhibit instability but no detectable mutations in these genes4–6. It is therefore of interest to identify other genes that contribute to this instability. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability7–11. Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12–14). Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites. Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides. A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene. Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair.

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Author notes

  1. John I. Risinger and Asad Umar: J.I.R. & A.U. contributed equally to this work

Authors and Affiliations

  1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709

    John I. Risinger & J. Carl Barrett

  2. Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    John I. Risinger & J. Carl Barrett

  3. Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709, USA

    Asad Umar & Thomas A. Kunkel

  4. Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA

    Jeff Boyd

  5. Department of Obstetrics and Gynecology/Division of Gynecologic Oncology, Duke University, Durham, North Carolina, 27710, USA

    Andrew Berchuck

Authors
  1. John I. Risinger
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  4. Andrew Berchuck
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  5. Thomas A. Kunkel
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  6. J. Carl Barrett
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Correspondence to Thomas A. Kunkel.

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Risinger, J., Umar, A., Boyd, J. et al. Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nat Genet 14, 102–105 (1996). https://doi.org/10.1038/ng0996-102

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