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.