A systematic pan-cancer analysis of somatic variants reveals epigenetic drivers of intra-tumor heterogeneity

Intra-tumor heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance. It results from the continuous evolution of different clones of a tumor over time. However, the molecular features underlying the emergence of genetically distinct subclonal cell populations remain elusive. Here, we conduct an exhaustive characterization of ITH across 2,807 tumor samples from 16 cancer types. Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetics modifier genes are the stronger determinants of ITH. In particular, genes that regulate genome-wide histone and DNA methylation emerged as candidate drivers of ITH. Knocking out the histone methyltransferase SETD2 or the DNA methyltransferase DNMT3A from cancer cells led to significant expansion of genetically distinct clones and culminated in highly heterogenous cell populations. Positively selected clones displayed similar mutational spectra and increased mitochondrial bioenergetic performance under stress conditions, suggesting that specific patterns of genotypic and phenotypic variation emerge upon epigenomic deregulation. Our work provides new insights on tumor development and unravels new drivers of ITH, which may be useful as either predictive biomarkers or therapeutic targets to improve cancer treatment.

肿瘤内异质性（Intra-tumor heterogeneity, ITH）是有效癌症治疗的主要障碍，也是耐药性产生的重要机制。其源于肿瘤不同克隆随时间推移的持续演化。然而，遗传特征迥异的亚克隆细胞群体出现背后的分子特征仍不明确。本研究对16种癌症类型的2807份肿瘤样本的ITH进行了全面表征。整合ITH评分与各肿瘤样本中检测到的体细胞变异后发现，表观遗传修饰基因的突变是ITH更强的决定因素。尤为关键的是，调控全基因组组蛋白与DNA甲基化的基因被鉴定为ITH的潜在驱动因子。敲除癌细胞中的组蛋白甲基转移酶SETD2或DNA甲基转移酶DNMT3A，会导致遗传迥异的克隆显著扩增，最终形成高度异质性的细胞群体。受正向选择的克隆在应激条件下展现出相似的突变谱，且线粒体生物能学性能提升，这表明表观基因组失调后会出现特定的基因型与表型变异模式。本研究为肿瘤发生发展提供了新见解，并揭示了ITH的全新驱动因子，这些因子或可作为预测生物标志物或治疗靶点，助力改善癌症治疗效果。