Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1 (original) (raw)

Nature Genetics volume 41, pages 112–117 (2009)Cite this article

Abstract

Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction2, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.

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Acknowledgements

We thank S. Wezenberg, M. Schliekelmann, E. Kamping, M. Steehouwer, R. Willems, A.S.Y. Chan, A.K.W. Chan, J.K.Y. Lau and C. Li for technical assistance, Diederik de Bruijn for advice and support, and clinicians in Hong Kong Hospital Authority for clinical care. This work was supported by research grants from the Dutch Cancer Society, the Research Grants Council of the Hong Kong Special Administrative Region (GRF HKU 7614/08M and HKU 7622/05M), the Hong Kong Cancer Fund and the Michael and Betty Kadoorie Cancer Genetics Research Programme.

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Author notes

  1. Marjolijn J L Ligtenberg, Roland P Kuiper and Tsun Leung Chan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
    Marjolijn J L Ligtenberg, Roland P Kuiper, Marsha Voorendt, Danielle Bodmer, Eveline Hoenselaar, Han G Brunner, Ad Geurts van Kessel & Nicoline Hoogerbrugge
  2. Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
    Marjolijn J L Ligtenberg, Monique Goossens, Konnie M Hebeda, Sandra J B Hendriks-Cornelissen & J Han J M van Krieken
  3. Department of Pathology, Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
    Tsun Leung Chan, Tracy Y H Lee, Wai Yin Tsui, Siu Tsan Yuen & Suet Yi Leung
  4. Department of Pathology, Hereditary Gastrointestinal Cancer Registry, St. Paul's Hospital, No 2 Eastern Hospital Road, Causeway Bay, Hong Kong
    Tsun Leung Chan, Siu Tsan Yuen & Suet Yi Leung
  5. Department of Surgery, Yan Chai Hospital, Nos. 7–11, Yan Chai Street, Tsuen Wan, New Territories, Hong Kong
    Chi Kwan Kong

Authors

  1. Marjolijn J L Ligtenberg
  2. Roland P Kuiper
  3. Tsun Leung Chan
  4. Monique Goossens
  5. Konnie M Hebeda
  6. Marsha Voorendt
  7. Tracy Y H Lee
  8. Danielle Bodmer
  9. Eveline Hoenselaar
  10. Sandra J B Hendriks-Cornelissen
  11. Wai Yin Tsui
  12. Chi Kwan Kong
  13. Han G Brunner
  14. Ad Geurts van Kessel
  15. Siu Tsan Yuen
  16. J Han J M van Krieken
  17. Suet Yi Leung
  18. Nicoline Hoogerbrugge

Contributions

M.J.L.L., R.P.K., T.L.C., S.T.Y. and S.Y.L. designed the study. For Dutch families, M.G. and S.J.B.H.-C. performed analyses on tumor and normal tissues; K.M.H. and J.H.J.M.v.K interpreted the histology and immunohistochemistry; D.B. and E.H. performed mutation, segregation and RT-PCR analyses; T.L.C. performed pyrosequencing; R.P.K. performed SNP-array analyses; M.V. and N.H. were responsible for patient counseling and clinical data acquisition; M.J.L.L., H.G.B., A.G.v.K., J.H.J.M.v.K. and N.H. supervised the work. For Hong Kong families, T.L.C., T.Y.H.L. and W.Y.T. performed experiments, C.K.K. provided clinical care and acquired clinical data; T.L.C., S.Y.L. and S.T.Y. analyzed and interpreted data; and M.J.L.L., R.P.K., T.L.C. and S.Y.L. wrote the manuscript, with assistance and final approval from all coauthors.

Corresponding authors

Correspondence toMarjolijn J L Ligtenberg or Suet Yi Leung.

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Ligtenberg, M., Kuiper, R., Chan, T. et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1.Nat Genet 41, 112–117 (2009). https://doi.org/10.1038/ng.283

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