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


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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Figure 1: A constitutional microdeletion of the TACSTD1 gene in Dutch families with MSH2-deficient tumors.
Figure 2: Deletion of the TACSTD1 gene in Chinese families with heritable MSH2 promoter methylation.
Figure 3: Allele-specific methylation of the MSH2 promoter coincides with TACSTD1 expression.

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  1. Lynch, H.T. & de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348, 919–932 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Barbour, V.M. et al. Alpha-thalassemia resulting from a negative chromosomal position effect. Blood 96, 800–807 (2000).

    CAS  PubMed  Google Scholar 

  3. Herman, J.G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA 95, 6870–6875 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kane, M.F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).

    CAS  PubMed  Google Scholar 

  5. Chen, H. et al. Evidence for heritable predisposition to epigenetic silencing of MLH1. Int. J. Cancer 120, 1684–1688 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Gazzoli, I., Loda, M., Garber, J., Syngal, S. & Kolodner, R.D. A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res. 62, 3925–3928 (2002).

    CAS  PubMed  Google Scholar 

  7. Suter, C.M., Martin, D.I. & Ward, R.L. Germline epimutation of MLH1 in individuals with multiple cancers. Nat. Genet. 36, 497–501 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Hitchins, M. et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129, 1392–1399 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Miyakura, Y. et al. Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin. Gastroenterol. Hepatol. 2, 147–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Valle, L. et al. MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin. Genet. 71, 232–237 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Hitchins, M.P. et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N. Engl. J. Med. 356, 697–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Morak, M. et al. Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur. J. Hum. Genet. 16, 804–811 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Chan, T.L. et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat. Genet. 38, 1178–1183 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Scherer, S.J., Seib, T., Seitz, G., Dooley, S. & Welter, C. Isolation and characterization of the human mismatch repair gene hMSH2 promoter region. Hum. Genet. 97, 114–116 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Iwahashi, Y. et al. Promoter analysis of the human mismatch repair gene hMSH2. Gene 213, 141–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. van der Klift, H. et al. Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosom. Cancer 44, 123–138 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Proudfoot, N. New perspectives on connecting messenger RNA 3′ end formation to transcription. Curr. Opin. Cell Biol. 16, 272–278 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Buratowski, S. Connections between mRNA 3′ end processing and transcription termination. Curr. Opin. Cell Biol. 17, 257–261 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Tufarelli, C. et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat. Genet. 34, 157–165 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Yu, W. et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451, 202–206 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Winter, M.J., Nagtegaal, I.D., van Krieken, J.H. & Litvinov, S.V. The epithelial cell adhesion molecule (Ep-CAM) as a morphoregulatory molecule is a tool in surgical pathology. Am. J. Pathol. 163, 2139–2148 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sivagnanam, M. et al. Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology 135, 429–437 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Overbeek, L.I. et al. Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. Br. J. Cancer 96, 1605–1612 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jeuken, J.W. et al. MS-MLPA: an attractive alternative laboratory assay for robust, reliable, and semiquantitative detection of MGMT promoter hypermethylation in gliomas. Lab. Invest. 87, 1055–1065 (2007).

    Article  CAS  PubMed  Google Scholar 

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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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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.

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Correspondence to Marjolijn 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).

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