Abstract 7415: Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment

Abstract Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. To evaluate the mutational signatures operative in a cancer genome, one first needs to quantify their activities by estimating the number of mutations imprinted by each signature, a process known as refitting of mutational signatures. Although multiple tools for refitting known signatures were developed in the past decade, most provide support almost exclusively for single base substitution signatures and lack an online interface. Further, these tools have never been compared, and no existing tool supports probabilistically assigning signatures to a single somatic mutation. Here, we present SigProfilerAssignment, a desktop and online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. The analysis of 2, 700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures, with consistent top performance across cancer types and most signatures. SigProfilerAssignment stands out as the most precise and sensitive tool while maintaining high computational performance and bringing novel capabilities. SigProfilerAssignment is distributed as an open-source Python/R package available at https: //github. com/AlexandrovLab/SigProfilerAssignment, with an online interface available as part of the COSMIC Mutational Signatures website at https: //cancer. sanger. ac. uk/signatures/assignment/. Citation Format: Raviteja Vangara, Marcos Diaz-Gay, Mark D. Barnes, Xi Wang, S M Ashiqul Islam, Ian Vermes, Stephen Duke, Nithish Bharadhwaj Narasimman, Ting Yang, Zichen Jiang, Sarah Moody, Sergey Senkin, Paul Brennan, Michael R. Stratton, Ludmil B. Alexandrov. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7415.