LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability.
LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability.
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DOI：
10.1371/journal.pone.0000399
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发表时间：
2007-05-02
期刊：
影响因子：
3.7
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
--
作者：
Estecio, Marcos R. H.;Gharibyan, Vazganush;Shen, Lanlan;Ibrahim, Ashraf E. K.;Doshi, Ketan;He, Rong;Jelinek, Jaroslav;Yang, Allen S.;Yan, Pearlly S.;Huang, Tim H-M.;Tajara, Eloiza H.;Issa, Jean-Pierre J.
癌症中DNA甲基化的改变包括整体低甲基化和基因特异性高甲基化。目前尚不清楚这两种表观遗传错误是机制上相关联还是独立发生。本研究旨在确定癌症中DNA低甲基化、高甲基化与微卫星不稳定性之间的关系。
我们使用LINE - 1亚硫酸氢盐 - PCR作为整体去甲基化的替代指标，检测了61个癌细胞系和60例结直肠癌及其邻近组织。散发性微卫星不稳定性（MSI）的结直肠癌，其中大多数是由于CpG岛甲基化表型（CIMP）以及相关的MLH1启动子甲基化，在正常邻近组织和癌组织之间LINE - 1甲基化平均无差异。有趣的是，该组中的一些肿瘤样本显示LINE - 1甲基化增加。相反，无MSI的在正常邻近组织和癌组织之间LINE - 1甲基化显著降低（P < 0.001）。对重复元件甲基化的微阵列分析证实了这一观察结果，并显示样本之间低甲基化存在高度变异性。此外，无监督层次聚类确定了一组高度低甲基化的肿瘤，主要由无微卫星不稳定性的肿瘤组成。我们将LINE - 1分析扩展到不同组织的癌细胞系，发现与外周血淋巴细胞和正常结肠黏膜相比，61个中有50个低甲基化。有趣的是，这些癌细胞系在去甲基化方面也表现出很大差异，这种差异具有组织特异性，因此不太可能是随机过程的结果。
在具有微卫星不稳定性的癌症中，整体低甲基化部分逆转，并且在癌症中也显示出高度变异性，这可能反映了癌症中的不同进展途径。
Alterations in DNA methylation in cancer include global hypomethylation and gene-specific hypermethylation. It is not clear whether these two epigenetic errors are mechanistically linked or occur independently. This study was performed to determine the relationship between DNA hypomethylation, hypermethylation and microsatellite instability in cancer. We examined 61 cancer cell lines and 60 colorectal carcinomas and their adjacent tissues using LINE-1 bisulfite-PCR as a surrogate for global demethylation. Colorectal carcinomas with sporadic microsatellite instability (MSI), most of which are due to a CpG island methylation phenotype (CIMP) and associated MLH1 promoter methylation, showed in average no difference in LINE-1 methylation between normal adjacent and cancer tissues. Interestingly, some tumor samples in this group showed increase in LINE-1 methylation. In contrast, MSI-showed a significant decrease in LINE-1 methylation between normal adjacent and cancer tissues (P<0.001). Microarray analysis of repetitive element methylation confirmed this observation and showed a high degree of variability in hypomethylation between samples. Additionally, unsupervised hierarchical clustering identified a group of highly hypomethylated tumors, composed mostly of tumors without microsatellite instability. We extended LINE-1 analysis to cancer cell lines from different tissues and found that 50/61 were hypomethylated compared to peripheral blood lymphocytes and normal colon mucosa. Interestingly, these cancer cell lines also exhibited a large variation in demethylation, which was tissue-specific and thus unlikely to be resultant from a stochastic process. Global hypomethylation is partially reversed in cancers with microsatellite instability and also shows high variability in cancer, which may reflect alternative progression pathways in cancer.
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影响因子：
50.3
作者：
Holm, TM;Jackson-Grusby, L;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
11.2
作者：
Yang, Allen S.;Doshi, Ketan D.;Issa, Jean-Pierre J.
通讯作者：
Issa, Jean-Pierre J.
影响因子：
78.5
作者：
Issa, JP
通讯作者：
Issa, JP
DOI：
10.1073/pnas.97.2.710
发表时间：
2000-01-18
影响因子：
11.1
作者：
Toyota, M;Ohe-Toyota, M;Issa, JPJ
通讯作者：
Issa, JPJ
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R