Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Correlation-based and feature-driven mutation signature analyses to identify genetic features associated with DNA mutagenic processes in cancer genomes

  • Jeong, Hye Young (Department of Medical Informatics, College of Medicine, The Catholic University of Korea) ;
  • Yoo, Jinseon (Department of Medical Informatics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Hyunwoo (Department of Medical Informatics, College of Medicine, The Catholic University of Korea) ;
  • Kim, Tae-Min (Department of Medical Informatics, College of Medicine, The Catholic University of Korea)
  • Received : 2021.08.19
  • Accepted : 2021.09.28
  • Published : 2021.12.31
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Abstract

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.

Keywords

Acknowledgement

This work was supported by the Korea Health Technology R&D Project via the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (HI15C3224) and by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2019R1A2C2002315).

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