Abstract B070: Chemotherapy is a major mutagen in relapsed childhood cancer
Authors: Layeghifard Mehdi , Light Nicholas , Bergstrom Erik , Gay Marcos Diaz , Mahendralingam Mathepan J. , Blay Sasha , Davidson Scott , Ballester Pedro L. , Hammad Rawan , Bolanos Noemi Fuentes , Nassif Shimaa , Thacker Nirav H. , Mayoh Chelsea , Malkin David , Papaemmanuil Elli , Cowley Mark J. , Villani Anita , Alexandrov Ludmil B. , Shlien Adam 
Published: September 2024

Abstract
Treatment at a young age places survivors of childhood cancers at a significantly elevated risk of developing life-threatening conditions such as cardiac dysfunction and secondary neoplasms. To better define the genomic impact of cancer therapy in children, we studied a diverse cohort of childhood tumors that had been heavily treated with multiple chemotherapies. We retrospectively collected detailed therapeutic data (including drug and dosage for each treatment cycle) for three cohorts of aggressive and hard-to-cure pediatric cancers: KiCS (The Hospital for Sick Children Toronto), ZCC (Zero Childhood Cancer, Sydney, Australia), and MSK (Memorial Sloan Kettering, New York, USA). We observed that therapy had a sizeable contribution to the mutation load in the treated samples, some of which could be detected in the form of mutational signatures. Performing a comprehensive signature analysis, we detected 69 mutational signatures, including 49 COSMIC and 20 novel signatures. We observed almost three times more exclusive signatures in treated tumors (14 vs 5 in untreated tumors). Excluding the hypermutator tumors, the difference became even more striking: 15 signatures were exclusively found in treated tumors while there were no signatures exclusive to treatment-naïve tumors. Platinum chemotherapies were the most potent DNA-damaging therapies – leading to the most somatic mutations, in the shortest time. In addition to known COSMIC platinum signatures, we found five novel putative signatures of platinum resistance. Using detailed therapy exposure data extracted from clinical charts, we found that a minimum 91 days and a burden of 0.5 mut/Mb were required to detect evidence of resistance. Nearly three quarters of the tumors passing both thresholds displayed the relevant resistance-associated signatures. Remarkably, over a third (35%) of tumors treated with platinum drugs displayed measurable resistance-associated mutations after just 12 months. This reached the 50% mark at the 33-month timepoint, then plateaued. Similar, albeit slower, trends were detected for other therapies. We also found that therapy signatures could appear at both clonal and subclonal levels as well as among clustered events. This multi-center analysis of heavily treated childhood tumors presents preliminary insights with potential to monitor drug resistance or interfere with its development.
Citation Format: Mehdi Layeghifard, Nicholas Light, Erik Bergstrom, Marcos Diaz Gay, Mathepan J. Mahendralingam, Sasha Blay, Scott Davidson, Pedro L. Ballester, Rawan Hammad, Noemi Fuentes Bolanos, Shimaa Nassif, Nirav H. Thacker, Chelsea Mayoh, David Malkin, Elli Papaemmanuil, Mark J. Cowley, Anita Villani, Ludmil B. Alexandrov, Adam Shlien. Chemotherapy is a major mutagen in relapsed childhood cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B070.