Nature Genetics
- 38, 1178 - 1183 (2006)
Published online: 3 September 2006; | doi:10.1038/ng1866
Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancerTsun Leung Chan1, 2, Siu Tsan Yuen1, 2, 3, Chi Kwan Kong4, Yee Wai Chan1, 2, Annie SY Chan1, Wai Fu Ng5, Wai Yin Tsui1, Michelle WS Lo1, Wing Yip Tam1, Vivian SW Li1 & Suet Yi Leung11
Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. 2
Hereditary Gastrointestinal Cancer Registry, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. 3
Department of Pathology, St. Paul's Hospital, No. 2 Eastern Hospital Road, Causeway Bay, Hong Kong. 4
Department of Surgery, Yan Chai Hospital, Nos. 7-11, Yan Chai Street, Tsuen Wan, New Territories, Hong Kong. 5
Department of Pathology, Yan Chai Hospital, Nos. 7-11, Yan Chai Street, Tsuen Wan, New Territories, Hong Kong.
Correspondence should be addressed to Suet Yi Leung suetyi@hkucc.hku.hk or Siu Tsan Yuen styuen@hkucc.hku.hk 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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