Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis.
Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis.
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DOI：
10.4236/jct.2014.514131
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发表时间：
2014-12-01
期刊：
影响因子：
--
通讯作者：
Bestor TH
中科院分区：
文献类型：
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作者：
O'Donnell AH;Edwards JR;Rollins RA;Vander Kraats ND;Su T;Hibshoosh HH;Bestor TH
肿瘤抑制基因的异位从头甲基化导致启动子沉默已被认为是与失活突变相当或等同的致癌因素。然而，这一假设之前并没有在原发性癌中通过高分辨率、高覆盖率的全基因组甲基化谱进行测试。我们通过检测超过27亿个CpG二核苷酸，确定了一系列原发性乳腺癌和匹配对照组织的基因组甲基化状态。大多数肿瘤显示所有序列区室DNA甲基化的不同损失，但启动子甲基化的增加很少，程度非常小，并且主要在CpG-poor启动子上观察到。原癌基因启动子和肿瘤抑制基因启动子的从头甲基化发生的频率大致相同。研究结果表明，由从头甲基化引起的肿瘤抑制基因沉默比目前认为的要少得多。我们提出了一种假设，即在癌症中常见的去甲基化是一种防御系统杀死早期癌细胞的表现。
Promoter silencing by ectopic de novo methylation of tumor suppressor genes has been proposed as comparable or equivalent to inactivating mutations as a factor in carcinogenesis. However, this hypotheses had not previously been tested by high resolution, high-coverage whole-genome methylation profiling in primary carcinomas. We have determined the genomic methylation status of a series of primary mammary carcinomas and matched control tissues by examination of more than 2.7 billion CpG dinucleotides. Most of the tumors showed variable losses of DNA methylation from all sequence compartments, but increases in promoter methylation were infrequent, very small in extent, and were observed largely at CpG-poor promoters. De novo methylation at the promoters of proto-oncogenes and tumor suppressor genes occurred at approximately the same frequency. The findings indicate that tumor suppressor silencing by de novo methylation is much less common than currently believed. We put forward a hypothesis under which the demethylation commonly observed in carcinomas is a manifestation of a defensive system that kills incipient cancer cells.