PT  - JOURNAL ARTICLE
AU  - Jin, Hu
AU  - Gulhan, Doga C.
AU  - Geiger, Benedikt
AU  - Ben-Isvy, Daniel
AU  - Geng, David
AU  - Ljungstrom, Viktor
AU  - Park, Peter J.
TI  - Accurate and sensitive mutational signature analysis with MuSiCal
AID  - 10.1101/2022.04.21.489082
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2022.04.21.489082
4099  - http://biorxiv.org/content/early/2023/12/07/2022.04.21.489082.short
4100  - http://biorxiv.org/content/early/2023/12/07/2022.04.21.489082.full
AB  - Mutational signature analysis is a recent computational approach for interpreting somatic mutations in the genome. Its application to cancer data has enhanced our understanding of mutational forces driving tumorigenesis and demonstrated its potential to inform prognosis and treatment decisions. However, methodological challenges remain for discovering new signatures and assigning proper weights to existing signatures, thereby hindering broader clinical applications. Here we present MuSiCal (Mutational Signature Calculator), a rigorous analytical framework with novel algorithms that solves major problems in the standard workflow. Our simulation studies demonstrate that MuSiCal outperforms state-of-the-art algorithms for both signature discovery and assignment. By reanalyzing over 2,700 cancer genomes, we provide an improved catalog of signatures and their assignments, discover nine indel signatures absent in the current catalog, resolve long-standing issues with the ambiguous ‘flat’ signatures, and give insights into signatures with unknown etiologies. We expect MuSiCal and the improved catalog to be a step towards establishing best practices for mutational signature analysis.Competing Interest StatementThe authors have declared no competing interest.