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JMG, Humans, Mutation, Neoplasms, Binding Sites, Transcription Factors, Gene Expression Regulation

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Nat Commun. 2023;14(1):913







This work was funded by the National Institutes of Health (NIH) grants R35 GM128625 awarded to J.I.F.B, R21 HG011289 and R01 AI51051 awarded to T.S., and R00HG008179 and R35HG011329 awarded to R.T.


Although >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.


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