Leveraging biochemical reactions to unravel functional impacts of cancer somatic variants affecting protein interaction interfaces
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Published:2022-11-30
Issue:
Volume:10
Page:1111
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ISSN:2046-1402
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Container-title:F1000Research
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language:en
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Short-container-title:F1000Res
Author:
Raimondi FrancescoORCID,
Burkhart Joshua G.ORCID,
Betts Matthew J.,
Russell Robert B.,
Wu GuanmingORCID
Abstract
Background: Considering protein mutations in their biological context is essential for understanding their functional impact, interpretation of high-dimensional datasets and development of effective targeted therapies in personalized medicine. Methods: We combined the curated knowledge of biochemical reactions from Reactome with the analysis of interaction-mediating 3D interfaces from Mechismo. In addition, we provided a software tool for users to explore and browse the analysis results in a multi-scale perspective starting from pathways and reactions to protein-protein interactions and protein 3D structures. Results: We analyzed somatic mutations from TCGA, revealing several significantly impacted reactions and pathways in specific cancer types. We found examples of genes not yet listed as oncodrivers, whose rare mutations were predicted to affect cancer processes similarly to known oncodrivers. Some identified processes lack any known oncodrivers, which suggests potentially new cancer-related processes (e.g. complement cascade reactions). Furthermore, we found that mutations perturbing certain processes are significantly associated with distinct phenotypes (i.e. survival time) in specific cancer types (e.g. PIK3CA centered pathways in LGG and UCEC cancer types), suggesting the translational potential of our approach for patient stratification. Our analysis also uncovered several druggable processes (e.g. GPCR signalling pathways) containing enriched reactions, providing support for new off-label therapeutic options. Conclusions: In summary, we have established a multi-scale approach to study genetic variants based on protein-protein interaction 3D structures. Our approach is different from previously published studies in its focus on biochemical reactions and can be applied to other data types (e.g. post-translational modifications) collected for many types of disease.
Funder
National Human Genome Research Institute
U.S. National Library of Medicine
Associazione Italiana per la Ricerca sul Cancro
Alexander von Humboldt-Stiftung
Italian Ministry of University and Research
Germany Research Foundation
Publisher
F1000 Research Ltd
Subject
General Pharmacology, Toxicology and Pharmaceutics,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine