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MSH2 genomic deletions are a frequent cause of HNPCC

Nature Genetics volume 20, pages 326–328 (1998)Cite this article

Hereditary non-polyposis colorectal cancer (HNPCC) is a common, autosomal dominant, cancer susceptibility condition characterized by early onset colorectal cancer1. HNPCC is caused by germline mutations in one of five DNA mismatch repair genes (MMR): MSH2 (ref. 2), MLH1 (Refs 3,4), PMS1 (ref. 5), PMS2 ( ref. 5) and MSH6 (Refs 6,7). To date, more than 200 different predisposing mutations in these genes have been characterized in HNPCC patients, the majority of which occur in MSH2 and MLH1 (ref. 8; see also http://www.nfdht.nl/index.htm). Here, we report that genomic deletions at MSH2 also represent a frequent cause of HNPCC. In fact, these deletions comprise more than one-third of all pathogenic MSH2 mutations among Dutch HNPCC families and account for 6.5% of HNPCC defined by the Amsterdam criteria.

Little is known about the number or location of Alu-repeats in MSH2, however, MSH2 deletions encompassing exon 1, exons 1-6 and exons 4-8 have been detected13,14,15. The presence of recurring deletions in several HNPCC families could be indicative of a founder mutation or of the independent occurrence of the same rearrangement due to the presence of recombinogenic sequences such as Alu repeats. Haplotype analysis of the kindreds sharing the same deletions failed to show evidence of a founder effect (data not shown). These observations indicate that the deletions reported here arose independently through a common recombination event.

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Figure 1: Mapping of MSH2 deletions responsible for HNPCC.
Figure 2: Nucleotide sequence analysis of deleted MSH2 transcripts.

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Acknowledgements

The authors are grateful to M. de Almeida for technical assistance and the following clinicians for contributing their HNPCC families: F. Nagengast, A. Bröcker-Vriends, G. Griffioen, A. Cats and J. Kleibeuker. This work has been supported in part by the Dutch Cancer Society and Praeventiefonds (project no. PRF 28-1383-1).

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Authors and Affiliations

  1. MGC-Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Juul Wijnen, Heleen van der Klift, P. Meera Khan & Ricardo Fodde.

  2. The Foundation for the Detection of Hereditary Tumors, and Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands

    Hans Vasen

  3. Department of Clinical Genetics, Free University Hospital, Amsterdam, The Netherlands

    Fred Menko

  4. Clinical Genetic Center Leiden, Leiden University Medical Center, Leiden, The Netherlands

    Carli Tops

  5. MGC-Department of Clinical Genetics, Erasmus University Rotterdam, Rotterdam, The Netherlands

    Hanne Meijers Heijboer & Dick Lindhout

  6. The Norwegian Radium Hospital, Oslo, Norway

    Pål Møller

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Wijnen, J., van der Klift, H., Vasen, H. et al. MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 20, 326–328 (1998). https://doi.org/10.1038/3795

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