Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer (original) (raw)

Nature Genetics volume 38, pages 1178–1183 (2006)Cite this article

Abstract

Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy.

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Acknowledgements

We thank V. Yu, K.C. Lee, J. Ho, B. Leung and E. Chan for sample coordination and clinical care; W.M. Ho and C.W. Wong for technical assistance; J. Sham and The Genome Research Centre of The University of Hong Kong for support and P.C. Sham for help with linkage analysis. This work was supported by research grants from the Hong Kong Cancer Fund and the Kadoorie Charitable Foundation.

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Authors and Affiliations

  1. Department of Pathology, Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
    Tsun Leung Chan, Siu Tsan Yuen, Yee Wai Chan, Annie SY Chan, Wai Yin Tsui, Michelle WS Lo, Wing Yip Tam, Vivian SW Li & Suet Yi Leung
  2. Hereditary Gastrointestinal Cancer Registry, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
    Tsun Leung Chan, Siu Tsan Yuen & Yee Wai Chan
  3. Department of Pathology, St. Paul's Hospital, No. 2 Eastern Hospital Road, Causeway Bay, Hong Kong
    Siu Tsan Yuen
  4. Department of Surgery, Yan Chai Hospital, Nos. 7-11, Yan Chai Street, Tsuen Wan, New Territories, Hong Kong
    Chi Kwan Kong
  5. Department of Pathology, Yan Chai Hospital, Nos. 7-11, Yan Chai Street, Tsuen Wan, New Territories, Hong Kong
    Wai Fu Ng

Authors

  1. Tsun Leung Chan
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  2. Siu Tsan Yuen
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  3. Chi Kwan Kong
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  4. Yee Wai Chan
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  5. Annie SY Chan
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  6. Wai Fu Ng
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  7. Wai Yin Tsui
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  8. Michelle WS Lo
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  9. Wing Yip Tam
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  10. Vivian SW Li
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  11. Suet Yi Leung
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Correspondence toSiu Tsan Yuen or Suet Yi Leung.

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Supplementary information

Supplementary Fig. 1

Immunohistochemical staining for MSH2. (PDF 77 kb)

Supplementary Fig. 2

Methylation-specific PCR screening for MSH2 promoter methylation in all family members. (PDF 369 kb)

Supplementary Fig. 3

Representative pyrosequencing chromatogram of the MSH2 promoter after bisulfite conversion and amplification by NP2, encompassing CpG sites 8-10. (PDF 96 kb)

Supplementary Table 1

Details of clinical information, MSI analysis, and MSH2 and MLH1 immunostaining results for the current family. (PDF 60 kb)

Supplementary Table 2

Clonal bisulfite allelic sequencing of blood leukocyte DNA from three healthy blood donors with a G/T polymorphism in SNP-433, using methylation-unbiased primers NP1 and NP2. (PDF 14 kb)

Supplementary Methods (PDF 27 kb)

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Chan, T., Yuen, S., Kong, C. et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer.Nat Genet 38, 1178–1183 (2006). https://doi.org/10.1038/ng1866

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