Mutational processes in cancer preferentially affect binding of particular transcription factors

Abstract

AbstractProtein binding microarrays provide comprehensive information about the DNA binding specificities of transcription factors (TFs), and can be used to quantitatively predict the effects of DNA sequence variation on TF binding. There has also been substantial progress in dissecting the patterns of mutations, i.e., the "mutational signatures", generated by different mutational processes. By combining these two layers of information we can investigate whether certain mutational processes tend to preferentially affect binding of particular classes of TFs. Such preferential alterations of binding might predispose to particular oncogenic pathways. We developed and implemented a method, termed "Signature-QBiC", that integrates protein binding microarray data with the signatures of mutational processes, with the aim of predicting which TFs’ binding profiles are preferentially perturbed by particular mutational processes. We used Signature-QBiC to predict the effects of 47 signatures of mutational processes on 582 human TFs. Pathway analysis showed that binding of TFs involved in NOTCH1 signaling is strongly affected by the signatures of several mutational processes, including exposure to ultraviolet radiation. Additionally, toll-like-receptor signaling pathways are also vulnerable to disruption by this exposure. This study provides a novel overview of the effects of mutational processes on TF binding and the potential of these processes to activate oncogenic pathways through mutating TF binding sites.