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Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

Nature Genetics 38, 1178–1183 (2006) | Download Citation

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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.

Author information

Affiliations

  1. Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, 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

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Siu Tsan Yuen or Suet Yi Leung.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Immunohistochemical staining for MSH2.

  2. 2.

    Supplementary Fig. 2

    Methylation-specific PCR screening for MSH2 promoter methylation in all family members.

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    Supplementary Fig. 3

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

  4. 4.

    Supplementary Table 1

    Details of clinical information, MSI analysis, and MSH2 and MLH1 immunostaining results for the current family.

  5. 5.

    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.

  6. 6.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ng1866

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