Utilising the totality of mutagenesis for clinical purposes

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.
References:

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.