Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02139, USA.
Broad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
Cancer Cell. 2014 Dec 8;26(6):813-825. doi: 10.1016/j.ccell.2014.10.012.
Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.
肿瘤内异质性在肿瘤进化中起着关键作用。为了确定 DNA 甲基化对肿瘤内异质性的贡献，我们对 104 例原发性慢性淋巴细胞白血病（CLL）进行了全基因组亚硫酸氢盐测序。与 26 例正常 B 细胞样本相比，CLL 样本在整个基因组中 DNA 甲基化模式的样本内变异性更高，这似乎是恶性细胞中随机无序的甲基化引起的。对 CLL 细胞的批量和单细胞转录组分析表明，甲基化紊乱与低水平表达有关。无序甲基化与不良的临床预后进一步相关。因此，我们提出，无序甲基化在增强癌细胞寻找更优进化轨迹的能力方面，起着类似于遗传不稳定性的作用。
