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Familial endometrial cancer in female carriers of MSH6 germline mutations

Nature Genetics volume 23, pages 142–144 (1999) Cite this article

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Hereditary non-polyposis colorectal cancer (HNPCC) is a common autosomal dominant condition characterized by early onset colorectal cancer as well as other tumour types at different anatomical sites1. HNPCC tumours often display a high level of genomic instability, characterized by changes in repeat numbers of simple repetitive sequences (microsatellite instability, MSI), which reflects the malfunction of the DNA mismatch repair machinery2,3. Accordingly, HNPCC was shown to be caused by germline mutations in the DNA mismatch repair genes (MMR) MSH2, MLH1, PMS1, PMS2 and MSH6 (refs 3, 4, 5, 6). So far, more than 220 predisposing mutations have been identified, most in MSH2 and MLH1 and in families complying with the clinical Amsterdam criteria3,7,8 (AMS+). Many HNPCC families, however, do not fully comply with these criteria, and in most cases the causative mutations are unknown.

Previously, we determined the prevalence of pathogenic mutations at MSH2 and MLH1 among 287 kindreds, of which 133 were AMS+ and 154 showed familial clustering of cancers reminiscent of HNPCC. Approximately one-half of AMS+ families revealed a predisposing mutation, whereas only 7% of AMS– families had a mutation in either gene8,9,10. Here we analyse MSH6 by denaturing gradient gel electrophoresis (DGGE) in the remaining 214 kindreds, 71 AMS+ and 143 AMS–, in which no MSH2 or MLH1 mutations were found. We identified 9 different MSH6 pathogenic germline mutations in 10 kindreds (Table 1). These mutations were scattered along the coding sequence of MSH6 and predict the truncation of its protein product. We found 7 of 10 MSH6 mutations in atypical HNPCC families not fulfilling the Amsterdam criteria (7/154, 4.5%). These kindreds display a very high frequency of atypical hyperplastic lesions and carcinomas of the endometrium: 73% in female MSH6 mutation carriers compared with 29% in MSH2 and 31% in MLH1. Moreover, delayed age of cancer onset and incomplete penetrance were characteristic clinical features of the MSH6 mutation carriers (see Table 3 and Fig. 1, http://genetics.nature.com/supplementary_info/).

Table 1 Truncating mutations at MSH6 in HNPCC
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Acknowledgements

We thank G.-J. van Ommen and N. de Wind for discussions; I. van Leeuwen-Cornelisse for collecting blood samples; and clinicians J. Apold, H. Brunner, G. Griffioen, J. Kleibeuker, F. Nagengast, J. Post, C. Schaap and B. Taal. This study has been supported by grants from the Dutch Cancer Society and Praeventiefonds, and by a grant (118571/320) from the Norges Forskningsraad to P.M.

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Authors and Affiliations

  1. MGC-Department of Human and Clinical Genetics,

    Juul Wijnen, Heleen van der Klift & Riccardo Fodde

  2. Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands

    Wiljo de Leeuw, Cees Cornelisse & Hans Morreau

  3. Foundation for the Detection of Hereditary Tumors and Department of Gastroenterology, LUMC, Leiden, The Netherlands

    Hans Vasen

  4. Unit of Medical Genetics, The Norwegian Radium Hospital, Oslo, Norway

    Pål Møller & Astrid Stormorken

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

    Hanne Meijers-Heijboer & Dick Lindhout

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

    Fred Menko

  7. Department of Surgery, Heinrich Heine University, Düsseldorf, Germany

    Sandra Vossen & Gabriela Möslein

  8. Clinical Genetics Center Leiden, LUMC, Leiden, The Netherlands

    Carli Tops & Annette Bröcker-Vriends

  9. Department of Medical Genetics, University of Groningen, Groningen, The Netherlands

    Ying Wu, Robert Hofstra & Rolf Sijmons

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  1. Juul Wijnen
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Correspondence to Riccardo Fodde.

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Wijnen, J., Leeuw, W., Vasen, H. et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23, 142–144 (1999). https://doi.org/10.1038/13773

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