Abstract PL2: Advances in the understanding and the applications of mutational signatures in human cells

Abstract

Abstract A cancer genome is an historical account of the mutagenic activity that has occurred throughout the development of the tumour. Indeed, every mutation matters. 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 informative. We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers. Recently, the intellectual framework of mutational signatures was extended to include six novel rearrangement signatures. Exploring this in >2,500 whole genome sequenced tumours of multiple tumour types, reveals how our early (and rather simplistic) thinking of mutational signatures, requires critical re-evaluation. There are more nuances than previously appreciated. Diving into the detail of individual mutational signatures, we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the landscape of cancer genomes. In some instances, our findings invite more thoughtful consideration of that relatively binary distinction between drivers and passengers. Furthermore, we demonstrate why our whole genome profiling methods could assist in taking things to a clinical level, with mutational signatures forming an additional weapon in the arsenal of cancer diagnostics and therapeutic stratification, in the modern war against cancer. Finally, we validate cancer mutational signatures using cell-based model systems and arrive at new realisations (unpublished). This powerful approach (humbles the analyst and) emphasises how biological exploration of big data still relies indispensably on experimental work to truly advance understanding. Citation Format: Nik-Zainal S. Advances in the understanding and the applications of mutational signatures in human cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PL2.