Hotspot propensity across mutational processes

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• dc.contributor.author Arnedo Pac, Claudia
• dc.contributor.author Muiños, Ferran
• dc.contributor.author González-Pérez, Abel
• dc.contributor.author López Bigas, Núria
• dc.date.accessioned 2025-04-03T06:09:33Z
• dc.date.available 2025-04-03T06:09:33Z
• dc.date.issued 2024
• dc.description.abstract The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.
• dc.description.sponsorship This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation has made available to the study. We acknowledge the technical contributions of Iker Reyes-Salazar and Loris Mularoni to HotspotFinder algorithm and annotations. NL-B acknowledges funding from the European Research Council (consolidator grant 682398) and the European Regional Development Fund/Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00) and Fundación Científica Asociación Española Contra el Cáncer (AECC) (GC16173697BIGA). This work has also been supported by the project “Discovering the molecular signatures of cancer PROMotion to INform prevENTion” (PROMINENT) funded by Cancer Research UK (CGCATF-2021/100008), National Cancer Institute (1OT2CA278668-01) and the Spanish Cancer Association, AECC. IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). CA-P was supported by “la Caixa” Foundation (ID 100010434) fellowship (LCF/BQ/ES18/11670011).
• dc.format.mimetype application/pdf
• dc.identifier.citation Arnedo-Pac C, Muiños F, Gonzalez-Perez A, Lopez-Bigas N. Hotspot propensity across mutational processes. Mol Syst Biol. 2024 Jan;20(1):6-27. DOI: 10.1038/s44320-023-00001-w
• dc.identifier.doi http://dx.doi.org/10.1038/s44320-023-00001-w
• dc.identifier.issn 1744-4292
• dc.identifier.uri http://hdl.handle.net/10230/70083
• dc.language.iso eng
• dc.publisher EMBO Press
• dc.relation.ispartof Mol Syst Biol. 2024 Jan;20(1):6-27
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/682398
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094095-B-I00
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Mutation rate variability
• dc.subject.keyword Mutation rate variability at single-nucleotide resolution
• dc.subject.keyword Mutational hotspot propensity
• dc.subject.keyword Mutational hotspots
• dc.subject.keyword Mutational signatures
• dc.title Hotspot propensity across mutational processes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion