DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors.
DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors.
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DOI：
10.1016/j.ccell.2015.07.012
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发表时间：
2015-09-14
期刊：
影响因子：
50.3
通讯作者：
Costello JF
中科院分区：
文献类型：
--
作者：
Mazor T;Pankov A;Johnson BE;Hong C;Hamilton EG;Bell RJA;Smirnov IV;Reis GF;Phillips JJ;Barnes MJ;Idbaih A;Alentorn A;Kloezeman JJ;Lamfers MLM;Bollen AW;Taylor BS;Molinaro AM;Olshen AB;Chang SM;Song JS;Costello JF
肿瘤细胞群体的进化史可以从基因改变的模式中重建出来。与稳定的遗传事件相比，表观遗传状态是可逆的，对微环境敏感，这引发了表观遗传信息是否同样可以用于发现肿瘤系统学的问题。我们研究了一组低级别胶质瘤及其患者匹配的复发病例中DNA甲基化的时空动态。在恶性进展为高级别胶质母细胞瘤的过程中，通过启动子低甲基化上调转录的基因丰富了细胞周期功能，与破坏G1/S细胞周期检查点的遗传变化平行进化。此外，系统表观遗传关系有力地重现了从体细胞突变中推断的系统发育模式。这些发现突显了在整个脑瘤进化过程中遗传和表观遗传事件的广泛相互依赖。
The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.