胚系表观突变与人类肿瘤  

Germ-line epimutations and human cancer

作　　者：吴浦嫄[1,2] 范怡梅[1,2] 王亚平[1,2] 

机构地区：[1]南京大学医学院医学遗传学研究室,江苏南京210093 [2]江苏省医学分子技术重点实验室,江苏南京210093

出　　处：《癌症》2009年第12期1236-1242,共7页Chinese Journal of Cancer

基　　金：江苏省自然科学基金项目(编号:BK2008269);江苏省国际科技合作计划项目(编号:BZ2008055)~~

摘　　要：表观突变是指表观遗传调控出现错误,导致正常情况下表达的基因沉默或者正常情况下沉默的基因转录表达。表观突变通常被认为是局部体细胞事件,一般只存在于病变组织。但是,最近几年关于遗传性非息肉性结直肠癌的研究发现,在部分患者中,所有检测的正常组织均存在MLH1单等位基因启动子区域CpG岛甲基化,并证实这种异常甲基化是肿瘤形成的病因。随后,关于其他抑癌基因MSH2与BRCA1等的胚系异常甲基化也陆续有报道。这提示,表观突变也可以起源于胚系(生殖细胞形成期或胚胎发育早期),从而造成全身细胞广泛的基因转录沉默。这种胚系表观突变类似于经典的基因胚系序列突变,可能成为人类疾病发生的病因。本文着重对近年来抑癌基因胚系表观突变研究进展作一综述,探讨胚系表观突变可能的产生机制和代间遗传的可能性,并展望其给人类疾病病因研究所带来的深远影响。Epimutations are errors in the normal process of epigenetic regulation which can result in aberrant transcriptional silencing of a normally active gene or reactivation of a normally silent gene. Epimutations are generally considered to be somatic events and to be confined in affected tissues. However, recent studies of patients with hereditary nonpolyposis colorectal cancer （HNPCC） have showed that allele-specific hypermethylation of CpG islands in the promoter region of the MLH1 gene, one of the causes of the tumor, existed in all the tissues examined. In addition, germ-line epimutations of other tumor suppressor genes （TSGs）, such as MSH2 and BRCA1, have also been reported, demonstrating that epimutations might arise in the germline （during gametogenesis or early embryonic development）. The role of germ-line epimutations might be as important as germ-line mutations in human disease. We reviewed the update on germ-line epimutations of TSGs including the possible mechanisms underlying germ-line epimutations, the possibility of transgenerational inheritance, and their impact on our understanding of human disease.

关 键 词：胚系表观突变 抑癌基因 高度甲基化 MLH1 

分 类 号：R730.2[医药卫生—肿瘤]