Abstract
BackgroundSomatic mutations in cancer genomes occur through a variety of molecular mechanisms, which contribute to different mutational patterns. To summarize these, mutational signatures have been defined using a large number of cancer genomes, and related to distinct mutagenic processes. Each cancer genome can be compared to this reference dataset and its exposure to one or the other signature be determined. Given the very different mutational patterns of these signatures, we anticipate that they will have distinct impact on genomic elements, in particular motifs for transcription factor binding sites (TFBS).MethodsWe used the 30 mutational signatures from the COSMIC database, and derived a theoretical framework to infer the impact of these signatures on the alteration of transcription factor (TF) binding motifs from the JASPAR database. Hence, we translated the trinucleotide mutation frequencies of the signatures into alteration frequencies of specific TF binding motifs, leading either to creation or disruption of these motifs.ResultsMotif families show different susceptibility to alterations induced by the mutational signatures. For certain motifs, a high correlation is observed between the TFBS motif creation and disruption events related to the information content of the motif. Moreover, we observe striking patterns regarding for example the Ets-motif family, for which a high impact of UV induced signatures is observed. Our model also confirms the susceptibility of specific transcription factor motifs to deamination processes.ConclusionOur results show that the mutational signatures have different impact on the binding motifs of transcription factors and that for certain high complexity motifs there is a strong correlation between creation and disruption, related to the information content of the motif. This study represents a background estimation of the alterations due purely to mutational signatures in the absence of additional contributions, e.g. from evolutionary processes.
Highlights
Somatic mutations in cancer genomes occur through a variety of molecular mechanisms, which contribute to different mutational patterns
We studied the composition of transcription factor (TF) motifs of each cluster
After this global analysis of the alteration patterns across all 512 motifs, we focused on specific motifs related to transcription factors which play a role in cancer
Summary
Somatic mutations in cancer genomes occur through a variety of molecular mechanisms, which contribute to different mutational patterns. Chan et al BMC Medical Genomics (2019) 12:64 shown to create new binding sites for Ets-family transcription factors, leading to a strong over-expression of the TERT oncogene [1, 2]. Another example was found in TALL, in which a mutation creating a new binding site for MYB leads to the appearance of a super-enhancer driving over-expression of the TAL1 oncogene [3] Besides these few non-coding drivers, cancer genomes are loaded with thousands of mutations which are termed passenger, as they cannot be individually related to molecular phenotypes, as in the previous cases. It is of importance to understand the overall patterns of non-coding mutations, besides the few driving examples
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