Chromosomal mutational signatures of DNA damaging agents at single cell resolution
Year: 2026
Type: preprint
Abstract: The chromosomal-scale mutational spectrum of small molecules that interact with DNA has been hard to study at scale, as mutational events are distributed in location and occur in parallel in different cells. Here, we present a framework that pairs phylogenetic ancestry reconstruction with mutational signature decomposition to characterise recent, cell-private copy number alteration (CNA) mutational patterns at single-cell resolution. We used this framework to characterise the cell-wise mutational spectrum of contemporaneous CNAs generated by double-strand-break-inducing chemotherapeutic drugs. We demonstrate that platinum salts, G-quadruplex stabilizers and topoisomerase II inhibitors, although mechanistically distinct, converge on a mutational signature dominated by telomere-bounded copy-number gains and losses. This signature is observed in different genetic backgrounds and in vivo in drug-treated patient-derived xenografts. We also observe a high rate of endogenous telomere-bounded mutational foreground in BRCA1 deficient cells. We show that the single cell genome derived signature exposures are drug dose-dependent, and use this to identify the decay of mutational load after drug withdrawal. We observe that both cisplatin and a G4 binder molecule (CX5461) exhibit foreground mutational signature persistence for at least 3 weeks after drug withdrawal, suggesting that residual effects of exposure may last longer than anticipated. Finally, extending the framework to serially drug-treated patient-derived xenograft (PDX) models, we show that telomere-bounded CNA signature exposure is associated with tumoural response to drug, consistent with loss of mutational activity on the genome after acquired resistance emerges. Together, our results show that our framework applied on scWGS identifies contemporaneous chromosomal mutation patterns induced by small molecules in human tissues.
Authors: Mirela Andronescu, Alexander Adrian-Hamazaki, Damian B Yap, William Daniels, Armaghan Sarvar, Elena Zaikova, Benjamin Furman, Vinci Au, Amelia Richter, Michael Van Vliet, Caroline Baril, Beixi Wang, Sean Beatty, Farhia Kabeer, Ciara O'Flanagan, Hoa Tran, Viktoriia Cherkasova, BaRun Kim, Teresa Ruiz De Algara, Sophia Means, Nat Westereng, Jay Tan, Jessica Chan, Johnson Zhong, Robert Reinert, Joseph Micla, Benoit Prevost-Potvin, Bita Mojtahedzadeh, Hong Xu, Richard Moore, Andy Mungall, Daniel Lai, Samuel Aparicio
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204187862