Abstract WS2-4: Clinical implications of tumor heterogeneity single cell genomics

Abstract

Abstract An understanding of how and why somatic mutations accumulate is required to shed light on cancer evolution. DNA replication during each cell cycle is an essential and highly regulated process that ensures the correct duplication of the entire genome. The timing of DNA replication has been indirectly linked to mutation acquisition and genome instability. However, the extent and the importance of altered replication timing (ART) from normal to cancer cells, and whether this process directly influences mutation acquisition during cancer evolution, have not been explored. Here we evaluated the impact of ART by analysing data from 1271 whole-genome sequenced lung (100,000 Genomes Project 1) and breast (560 breast cancer genomes from Nik-Zainal et al. 2) tumours, together with replication-timing sequencing data of multiple cancer and normal cell lines. We find that 6%-18% of the genome is subject to ART in cancer cells. Genomic regions subject to a shift from early to late replication in cancer cells exhibit an increased mutation rate in tumours and are associated with distinct mutational signatures compared to unaltered early replicated regions. In particular, we identify APOBEC3-mediated mutation clusters (omikli events) in unaltered early and late-to-early ART regions, associated with the acquisition of driver mutations. We demonstrate that ART is a relatively early event during the evolution of breast cancer and lung adenocarcinomas. Finally, genes replicated early in cancer but late in normal cells exhibit an up-regulated expression in tumour samples. The incorporation of single-cell DNA sequencing further enables accurate identification of proliferation rates. Taken together, replication timing alterations during malignant transformation are prevalent in cancer and significantly impact the genomic and transcriptomic landscape during tumour evolution. Citation Format: Nnennaya Kanu. Clinical implications of tumor heterogeneity single cell genomics [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-4.