Abstract 2858: Pleiotropy of experimental signatures across species and model systems

Mutational signatures in cancer genomes provide crucial insights into the etiology and progression of malignancies. While numerous signatures have been identified, many lack known causes, hindering our understanding of cancer development. This study presents a comprehensive analysis of mutational patterns induced by diverse environmental agents across multiple model systems. We compiled data from over 4,000 genome-wide sequencing experiments, exposing various biological models—including human cell lines, rodent tumors, avian cells, and C. elegans—to more than 120 different agents under controlled conditions. By comparing mutational profiles across 30+ model systems, we identified significant inter-model disparities, underscoring the importance of diverse experimental approaches in confidently characterizing mutational signatures observed in human cancers. Our findings enhance the interpretation of clinical and epidemiological data related to specific carcinogen exposures and provide a robust framework for elucidating the role of environmental factors in cancer etiology. This research contributes to a more nuanced understanding of the complex interplay between environmental exposures, genetic susceptibility, and cancer development, potentially informing novel prevention strategies and therapeutic interventions. Citation Format: Maria Zhivagui, Shams Al-azzam, Mark Barnes, Ludmil B. Alexandrov. Pleiotropy of experimental signatures across species and model systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2858.