Germline epimutation of MLH1 in individuals with multiple cancers
Germline epimutation of MLH1 in individuals with multiple cancers
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DOI：
10.1038/ng1342
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发表时间：
2004-05-01
期刊：
影响因子：
30.8
通讯作者：
Ward, RL
中科院分区：
文献类型：
--
作者：
Suter, CM;Martin, DIK;Ward, RL
表观遗传沉默可以通过取消基因的表达来模仿基因突变。我们假设，任何基因都可能发生突变，这是一种容易引发疾病的生殖系事件，并在癌症患者的肿瘤抑制基因中寻找了例子。在这里，我们报告了两个个体的DNA错配修复基因MLH1的体细胞范围、等位基因特异性和镶嵌超甲基化。这两个人都缺乏任何错配修复基因的基因突变证据，但都有表现出错配修复缺陷的多个原发肿瘤，而且都符合遗传性非息肉病性结直肠癌的临床标准。在其中一名个体的精子中也出现了这种表亲突变，这表明存在生殖系缺陷，并有可能传递给后代。生殖系突变为遗传病的表型复制提供了一种机制。表观遗传状态特有的马赛克和非孟德尔遗传可能会产生类似于多基因或复杂性状的疾病风险模式。
Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. We hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. Here we report two individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lack evidence of genetic mutation in any mismatch repair gene but have had multiple primary tumors that show mismatch repair deficiency, and both meet clinical criteria for hereditary nonpolyposis colorectal cancer. The epimutation was also present in spermatozoa of one of the individuals, indicating a germline defect and the potential for transmission to offspring. Germline epimutation provides a mechanism for phenocopying of genetic disease. The mosaicism and nonmendelian inheritance that are characteristic of epigenetic states could produce patterns of disease risk that resemble those of polygenic or complex traits.