title: Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer.
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.
authors.affiliation: Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Tsun Leung
authors.initials: TL
authors.lastname: Chan
authors.forename: Siu Tsan
authors.initials: ST
authors.lastname: Yuen
authors.forename: Chi Kwan
authors.initials: CK
authors.lastname: Kong
authors.forename: Yee Wai
authors.initials: YW
authors.lastname: Chan
authors.forename: Annie S Y
authors.initials: AS
authors.lastname: Chan
authors.forename: Wai Fu
authors.initials: WF
authors.lastname: Ng
authors.forename: Wai Yin
authors.initials: WY
authors.lastname: Tsui
authors.forename: Michelle W S
authors.initials: MW
authors.lastname: Lo
authors.forename: Wing Yip
authors.initials: WY
authors.lastname: Tam
authors.forename: Vivian S W
authors.initials: VS
authors.lastname: Li
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
mesh_terms: D000328:Adult; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010375:Pedigree
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein