Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.
Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.
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DOI：
10.1016/j.ccell.2014.10.012
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发表时间：
2014-12-08
期刊：
影响因子：
50.3
通讯作者：
Wu CJ
中科院分区：
文献类型：
--
作者：
Landau DA;Clement K;Ziller MJ;Boyle P;Fan J;Gu H;Stevenson K;Sougnez C;Wang L;Li S;Kotliar D;Zhang W;Ghandi M;Garraway L;Fernandes SM;Livak KJ;Gabriel S;Gnirke A;Lander ES;Brown JR;Neuberg D;Kharchenko PV;Hacohen N;Getz G;Meissner A;Wu CJ
肿瘤内异质性在肿瘤演变中起关键作用。为了确定DNA甲基化对肿瘤异质性的贡献，我们对104例原发性慢性淋巴细胞白血病（CLL）进行了基因组规模的亚硫酸氢盐测序。与26个正常B细胞样品相比，CLL在整个基因组中始终显示出较高的DNA甲基化模式的样品内变异性，这似乎是由恶性细胞中的随机无序甲基化引起的。对大块和单个CLL细胞的转录组分析显示，甲基化障碍与低水平表达有关。异常甲基化进一步与不良临床结果相关。因此，我们提出，无序甲基化起着类似于遗传不稳定性的作用，增强了癌细胞寻找上级进化轨迹的能力。
Intra-tumoral 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 (CLL). Compared to 26 normal B cell samples, CLLs consistently displayed higher intra-sample 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 genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.
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