Chan Tsun Leung, Yuen Siu Tsan, Kong Chi Kwan, Chan Yee Wai, Chan Annie S Y, Ng Wai Fu, Tsui Wai Yin, Lo Michelle W S, Tam Wing Yip, Li Vivian S W, Leung Suet Yi
Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Nat Genet. 2006 Oct;38(10):1178-83. doi: 10.1038/ng1866. Epub 2006 Sep 3.
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.
生殖系中的表观突变，如MLH1基因的甲基化，可能导致人类遗传性癌症综合征，但其向后代的传递从未有过记录。在此，我们报告一个家族，其连续三代存在生殖系MSH2基因的等位基因特异性和嵌合性高甲基化，且无DNA错配修复基因突变的证据。携带生殖系甲基化的三名兄弟姐妹患早发性结直肠癌或子宫内膜癌，均伴有微卫星不稳定性和MSH2蛋白缺失。克隆亚硫酸氢盐测序和焦磷酸测序显示不同体细胞组织中的甲基化水平不同，直肠黏膜和结肠癌组织中的甲基化水平最高，血液白细胞中的最低。这种具有不同组织分布的生殖系甲基化嵌合状态可能作为首次打击，并为可能偏离孟德尔模式且在传统基于白细胞的基因诊断策略中被忽视的遗传疾病遗传提供一种机制。
