Impact of cancer mutational signatures on transcription factor motifs in the human genome

BMC Medical Genomics

Zuguang Gu¹  Calvin Wing Yiu Chan²  Carl Herrmann³  Matthias Bieg⁴  Roland Eils⁵ 

[1] 0000 0004 0492 0584, grid.7497.d, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;0000 0004 0492 0584, grid.7497.d, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;0000 0001 2190 4373, grid.7700.0, Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany;0000 0004 0492 0584, grid.7497.d, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, 69120, Heidelberg, Germany;0000 0004 0492 0584, grid.7497.d, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;grid.484013.a, Center for Digital Health, Berlin Institute of Health (BIH), 10178, Berlin, Germany;0000 0004 0492 0584, grid.7497.d, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;grid.484013.a, Center for Digital Health, Berlin Institute of Health (BIH), 10178, Berlin, Germany;Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, 69120, Heidelberg, Germany;

关键词: SNV;    Cancer;    Mutational signature;   

DOI  :  10.1186/s12920-019-0525-4

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY