A cancer genome carries the historic mutagenic activity that has occurred throughout the development of a tumour1. While driver mutations were the main focus of cancer research for a long time, passenger mutational signatures – the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis – are also biologically informative1,2. In this lecture, I provide a synopsis of this concept, describe the insights that we have gained through combinations of computational analysis3,4 and experiments in cell-based systems5, and showcase how we have developed the concept into applications that we hope to translate into clinical utility in the near future3,4. I describe our efforts in a population-derived cohort as well as in individual patients, emphasizing the need for us to be more precise in analyses and interpretation in human cancer genomics.
1. Helleday T, Eshtad S, Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers.Nat Rev Genet. 2014 Sep;15(9):585-98. doi: 10.1038/nrg3729. Epub 2014 Jul 1. Review. PubMed PMID: 24981601; PubMed Central PMCID: PMC6044419.
2. Alexandrov LB, Nik-Zainal S, et al. Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477. Epub 2013 Aug 14. Erratum in: Nature. 2013 Oct 10;502(7470):258. Imielinsk, Marcin [corrected to Imielinski, Marcin]. PubMed PMID: 23945592; PubMed Central PMCID: PMC3776390.
3. Nik-Zainal S, Davies H, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016 Jun 2;534(7605):47-54. doi: 10.1038/nature17676. Epub 2016 May 2. PubMed PMID: 27135926; PubMed Central PMCID: PMC4910866.
4. Davies H, Glodzik D, et al. and Nik-Zainal S. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017 Apr;23(4):517-525. doi: 10.1038/nm.4292. Epub 2017 Mar 13. PubMed PMID: 28288110; PubMed Central PMCID: PMC5833945.
5. Zou X, Owusu M, Harris R, Jackson SP, Loizou JI, Nik-Zainal S. Validating the concept of mutational signatures with isogenic cell models. Nat Commun. 2018 May 1;9(1):1744. doi: 10.1038/s41467-018-04052-8. PubMed PMID: 29717121; PubMed Central PMCID: PMC5931590.