Non-genomic determinants of tumor cell phenotypes in adult glioblastoma.

Abstract Non-genomic determinates of oncogenic cellular phenotypes is an emerging concept that expanded our model of tumor hallmarks. We hypothesized that oncogenic programs in adult glioblastoma (GBM) such as angiogenesis, proliferation, DNA repair, epithelial to mesenchymal transition and quiescent states are achieved independently of mutational background or clonal linage. We therefore explored the assortations of large-scale chromosomal rearrangements and canonical driver mutations with oncogenic programs in single cell RNA sequencing (scRNA-seq) of over 3000 tumor cells in 4 adult GBM using open data. We find recurring patterns where tumor cells from diverse mutational background and clonal linage converge upon oncogenic tumor phenotypes. We validate this observation in 9 tumors comprising over 16,000 cells and in xenograft animal models of GBM pre- and post temozolamide treatment. We finally explore the epigenetic associations of oncogenic phenotypes via computational label transfer from scRNA-seq to chromatic accessibility data from single cell ATAC sequencing (scATAC-seq). We find open genomic regions associated with canonical regulators, such as the highly oncogenic mesenchymal phenotype driven by TWIST1. Our results suggest a paradigm shift towards non-genetic determinants of oncogenic phenotypes in GBM complementing the conventional concept of cancer clonal evolution.