Divisions of 1Epigenomics and Cancer Risk Factors, 2Theoretical Bioinformatics, 3Biostatistics, and 4Molecular Genetics; 5Department of Translational Oncology, National Center for Tumor Diseases (NCT), The German Cancer Research Center (DKFZ); 6Department of Medicine V, University of Heidelberg, Heidelberg; 7Department of Medicine, University of Freiburg Medical Center, Freiburg; 8Department of Internal Medicine III, University of Ulm, Ulm; 9The German Cancer Consortium, Germany; 10Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, California; and 11Division of Hematology, The Ohio State University, Columbus, Ohio.
Cancer Discov. 2014 Mar;4(3):348-61. doi: 10.1158/2159-8290.CD-13-0349. Epub 2013 Dec 19.
Although clonal selection by genetic driver aberrations in cancer is well documented, the ability of epigenetic alterations to promote tumor evolution is undefined. We used 450k arrays and next-generation sequencing to evaluate intratumor heterogeneity and evolution of DNA methylation and genetic aberrations in chronic lymphocytic leukemia (CLL). CLL cases exhibit vast interpatient differences in intratumor methylation heterogeneity, with genetically clonal cases maintaining low methylation heterogeneity and up to 10% of total CpGs in a monoallelically methylated state. Increasing methylation heterogeneity correlates with advanced genetic subclonal complexity. Selection of novel DNA methylation patterns is observed only in cases that undergo genetic evolution, and independent genetic evolution is uncommon and is restricted to low-risk alterations. These results reveal that although evolution of DNA methylation occurs in high-risk, clinically progressive cases, positive selection of novel methylation patterns entails coevolution of genetic alteration(s) in CLL.
尽管癌症中遗传驱动突变的克隆选择已得到充分证实，但表观遗传改变促进肿瘤进化的能力尚未确定。我们使用 450k 阵列和下一代测序来评估慢性淋巴细胞白血病 (CLL) 中肿瘤内异质性和 DNA 甲基化及遗传异常的演变。CLL 病例在肿瘤内甲基化异质性方面表现出巨大的个体间差异，遗传克隆病例保持低甲基化异质性，多达 10%的总 CpG 呈单等位基因甲基化状态。甲基化异质性的增加与先进的遗传亚克隆复杂性相关。只有在经历遗传进化的病例中才观察到新的 DNA 甲基化模式的选择，而独立的遗传进化并不常见，仅限于低风险改变。这些结果表明，尽管 DNA 甲基化的进化发生在高危、临床进展的病例中，但新的甲基化模式的正选择需要 CLL 中遗传改变的共同进化。
