Direct genetic transformation bypasses tumor-associated DNA methylation alterations (target enrichment)

Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, key unresolved questions remain about the conditions that support their initial transformation, which cannot be easily captured in patient populations but are instead modeled using transgenic cellular or animal systems. Here, we used extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and used this benchmark to screen 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation can trigger global changes in DNA methylation levels that are consistent with extensive proliferation but rarely recapitulate the widespread de novo methylation of Polycomb targets as found in clinical samples. Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis and provide an important molecular reference for evaluating existing as well as newer tumor models. Overall design: DNA methylation profiling of mouse models of cancer.

肿瘤是一类动态演化的突变细胞群体，学界在阐明其进展的生物学机制方面已取得诸多进展。然而，关于支持肿瘤初始转化的关键条件，仍存在诸多未决问题。此类条件难以在患者群体中直接观测，因此需借助转基因细胞或动物模型系统开展模拟研究。本研究依托大规模患者全景图谱数据，明确了肿瘤相较于正常人类细胞的DNA甲基化景观（DNA methylation landscape）共性特征，并以此为基准筛选了21种工程化构建的人类与小鼠模型，评估其能否复现上述甲基化特征模式。值得注意的是，本研究发现，遗传诱导的细胞转化可引发与细胞大规模增殖相符的DNA甲基化水平整体改变，但极少能复现临床样本中观察到的、Polycomb（多梳蛋白）靶基因的广泛从头甲基化现象。本研究结果针对肿瘤发生过程中遗传与表观遗传调控的关联提出了相关关键问题，同时为评估现有及新型肿瘤模型提供了重要的分子参照基准。整体实验设计：癌症小鼠模型的DNA甲基化谱分析。