Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers
Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers
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DOI：
10.1073/pnas.96.22.12661
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Peltomäki, P
中科院分区：
文献类型：
--
作者：
Kuismanen, SA;Holmberg, MT;Peltomäki, P
异常DNA甲基化是人类癌症中的常见现象，但其模式、原因和后果尚不清楚。DNA错配修复基因MutL同源物（MLH1）的启动子甲基化与显示微卫星不稳定性（MSI）的结直肠癌亚群有关。目前对89例散发性结直肠癌中MLH1启动子区域的4个MspI/ hall位点的分析揭示了两种与肿瘤MSI状态密切相关的主要甲基化模式。在大多数MSI（+）病例中，这些位点在肿瘤组织中相对于正常粘膜高度甲基化（31/51,61%）。相比之下，在大多数MSI（-）病例中（20/38）。53%)正常粘膜相同部位出现甲基化，肿瘤组织出现低甲基化。高甲基化与年龄增长和肠近端位置直接相关，并伴有肿瘤和正常组织中免疫组织化学记录的MLH1蛋白丢失。在降钙素基因的启动子区域观察到类似的甲基化模式，该基因在肿瘤发生中没有已知的功能作用。我们提出了一个致癌模型，其中不同的表观遗传表型区分了MSI（+）和MSI（-）肿瘤个体的结肠粘膜。这些表型可能是已知在这些肿瘤中发生的不同发育途径的基础。
Aberrant DNA methylation is a common phenomenon in human cancer, but its patterns, causes, and consequences are poorly defined. Promoter methylation of the DNA mismatch repair gene MutL homologue (MLH1) has been implicated in the subset of colorectal cancers that shows microsatellite instability (MSI). The present analysis of four MspI/Hpall sites at the MLH1 promoter region in a series of 89 sporadic colorectal cancers revealed two main methylation patterns that closely correlated with the MSI status of the tumors. These sites were hypermethylated in tumor tissue relative to normal mucose in most MSI(+) cases (31/51, 61%). By contrast, in the majority of MSI(-) cases (20/38. 53%)the same sites showed methylation in normal mucosa and hypomethylation in tumor tissue. Hypermethylation displayed a direct correlation with increasing age and proximal location in the bowel and was accompanied by immunohistochemically documented loss of MLH1 protein both in tumors and in normal tissue. Similar patterns of methylation were observed in the promoter region of the calcitonin gene that does not have a known functional role in tumorigenesis. We propose a model of carcinogenesis where different epigenetic phenotypes distinguish the colonic mucosa in individuals who develop MSI(+) and MSI(-) tumors. These phenotypes may underlie the different developmental pathways that are known to occur in these tumors.