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Transcription Factor-Centric Approach to Identify Non-recurring Putative Regulatory Drivers in Cancer

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Research in Computational Molecular Biology (RECOMB 2022)

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 13278))

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Abstract

Recent efforts to sequence the genomes of thousands of matched normal-tumor samples have led to the identification of millions of somatic mutations, the majority of which are non-coding. Most of these mutations are believed to be passengers, but a small number of non-coding mutations could contribute to tumor initiation or progression, e.g. by leading to dysregulation of gene expression. Efforts to identify putative regulatory drivers rely primarily on information about the recurrence of mutations across tumor samples. However, in regulatory regions of the genome, individual mutations are rarely seen in more than one donor. Instead of using recurrence information, here we present a method to prioritize putative regulatory driver mutations based on the magnitude of their effects on transcription factor-DNA binding. For each gene, we integrate the effects of mutations across all its regulatory regions, and we ask whether these effects are larger than expected by chance, given the mutation spectra observed in regulatory DNA in the cohort of interest. We applied our approach to analyze mutations in a liver cancer data set with ample somatic mutation and gene expression data available. By combining the effects of mutations across all regulatory regions of each gene, we identified dozens of genes whose regulation in tumor cells is likely to be significantly perturbed by non-coding mutations. Overall, our results show that focusing on the functional effects of non-coding mutations, rather than their recurrence, has the potential to prioritize putative regulatory drivers and the genes they dysregulate in tumor cells.

J. Zhao and V. Martin—The authors contributed equally to this work.

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Author information

Authors and Affiliations

  1. Center for Genomic and Computational Biology, Duke University, Durham, NC, 27708, USA

    Jingkang Zhao, Vincentius Martin & Raluca Gordân

  2. Program in Computational Biology and Bioinformatics, Duke University, Durham, NC, 27708, USA

    Jingkang Zhao & Raluca Gordân

  3. Department of Computer Science, Duke University, Durham, NC, 27708, USA

    Vincentius Martin & Raluca Gordân

  4. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, 27708, USA

    Raluca Gordân

  5. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, 27708, USA

    Raluca Gordân

Authors
  1. Jingkang Zhao
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  2. Vincentius Martin
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  3. Raluca Gordân
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Corresponding author

Correspondence to Raluca Gordân .

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Editors and Affiliations

  1. Columbia University, New York, NY, USA

    Itsik Pe'er

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Zhao, J., Martin, V., Gordân, R. (2022). Transcription Factor-Centric Approach to Identify Non-recurring Putative Regulatory Drivers in Cancer. In: Pe'er, I. (eds) Research in Computational Molecular Biology. RECOMB 2022. Lecture Notes in Computer Science(), vol 13278. Springer, Cham. https://doi.org/10.1007/978-3-031-04749-7_3

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  • DOI: https://doi.org/10.1007/978-3-031-04749-7_3

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-04748-0

  • Online ISBN: 978-3-031-04749-7

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