Authors: Sebastian Carrasco Pro, Heather Hook, David Bray, Daniel Berenzy, Devlin Moyer, Meimei Yin, Adam Thomas Labadorf, Ryan Tewhey, Trevor Siggers, Juan Ignacio Fuxman Bass
Published: 2023-02-17
DOI: 10.1038/s41467-023-36535-8
Source: Full article
AbstractAlthough >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a transcription factor (TF)-aware burden test based on a model of coherent TF function in promoters. We apply this test to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predict 2555 driver NCVs in the promoters of 813 genes across 20 cancer types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We find that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.