Abstract IA15: Single cell origins and targeting of genomic instability in breast cancers

Abstract

Abstract Early whole genome sequencing studies have emphasised the different modes by which breast cancers can evolve. However, bulk NGS tissue analysis obscures mutations that are contemporaneous and/or lead to negative selection, and does not resolve clone specific metrics such as replication rate and fitness. We have developed single cell genome sequencing methods (Laks et al., Cell 2019) to identify large scale copy number-structural (CNA-SV) mutational processes that result in genomic shuffling through the duplication or deletion of chromosomal regions, obscured by bulk tissue analysis. This has revealed the existence and activity of distinct “foreground” mutational processes, i.e. mutational events in single mitoses that are observed directly, before the effects of purifying selection. We discovered that foreground processes are preferentially associated with background patterns of genome instability (Funnell et al., Nature 2022). We also discovered that CNA-SV mutational patterns are associated with relative sensitivity or resistance to platinum, a commonly used DNA targeting agent in TNBC and HGSOC. Our second recent discovery has been the association of CNA-SV mutations with clonal resistance to platinum in TNBC (Salehi et al., Nature 2021). Taken together, we now understand that ongoing CNA-SV mutations contribute to the evolution of fitness landscapes for DNA targeting therapeutics. In parallel work (Xu et al Nat. comms 2017) we have discovered stabilisers of folded DNA guanine stacked bases, G-quadruplexes (G4), to be synthetically lethal in contexts including HR and TMEJ that are underpinned by the single cell processes identified through single genome sequencing. To this end we have recently observed G4-ligand clinical activity in BRCA2 and PALB2 mutated cancers in a phase 1 trial (Hilton et al, Nature communication 2022). Citation Format: Samuel Aparicio. Single cell origins and targeting of genomic instability in breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA15.