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Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

BACKGROUND: Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be stro...

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Autores principales: Belikov, Aleksey V., Vyatkin, Alexey D., Leonov, Sergey V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9375969/
https://www.ncbi.nlm.nih.gov/pubmed/35975235
http://dx.doi.org/10.7717/peerj.13860
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author Belikov, Aleksey V.
Vyatkin, Alexey D.
Leonov, Sergey V.
author_facet Belikov, Aleksey V.
Vyatkin, Alexey D.
Leonov, Sergey V.
author_sort Belikov, Aleksey V.
collection PubMed
description BACKGROUND: Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. METHODS: We propose formulas for the Driver Strength Index (DSI) and the Normalized Driver Strength Index (NDSI), the latter independent of gene mutation frequency. We validate them using TCGA PanCanAtlas datasets, established driver prediction algorithms and custom computational pipelines integrating SNA, CNA and aneuploidy driver contributions at the patient-level resolution. RESULTS: DSI and especially NDSI provide substantially different gene rankings compared to the frequency approach. E.g., NDSI prioritized members of specific protein families, including G proteins GNAQ, GNA11 and GNAS, isocitrate dehydrogenases IDH1 and IDH2, and fibroblast growth factor receptors FGFR2 and FGFR3. KEGG analysis shows that top NDSI-ranked genes comprise EGFR/FGFR2/GNAQ/GNA11–NRAS/HRAS/KRAS–BRAF pathway, AKT1–MTOR pathway, and TCEB1–VHL–HIF1A pathway. CONCLUSION: Our indices are able to select for driver gene attributes not selected by frequency sorting, potentially for driver strength. Genes and pathways prioritized are likely the strongest contributors to cancer initiation and progression and should become future therapeutic targets.
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spelling pubmed-93759692022-08-15 Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients Belikov, Aleksey V. Vyatkin, Alexey D. Leonov, Sergey V. PeerJ Bioinformatics BACKGROUND: Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. METHODS: We propose formulas for the Driver Strength Index (DSI) and the Normalized Driver Strength Index (NDSI), the latter independent of gene mutation frequency. We validate them using TCGA PanCanAtlas datasets, established driver prediction algorithms and custom computational pipelines integrating SNA, CNA and aneuploidy driver contributions at the patient-level resolution. RESULTS: DSI and especially NDSI provide substantially different gene rankings compared to the frequency approach. E.g., NDSI prioritized members of specific protein families, including G proteins GNAQ, GNA11 and GNAS, isocitrate dehydrogenases IDH1 and IDH2, and fibroblast growth factor receptors FGFR2 and FGFR3. KEGG analysis shows that top NDSI-ranked genes comprise EGFR/FGFR2/GNAQ/GNA11–NRAS/HRAS/KRAS–BRAF pathway, AKT1–MTOR pathway, and TCEB1–VHL–HIF1A pathway. CONCLUSION: Our indices are able to select for driver gene attributes not selected by frequency sorting, potentially for driver strength. Genes and pathways prioritized are likely the strongest contributors to cancer initiation and progression and should become future therapeutic targets. PeerJ Inc. 2022-08-11 /pmc/articles/PMC9375969/ /pubmed/35975235 http://dx.doi.org/10.7717/peerj.13860 Text en © 2022 Belikov et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Bioinformatics
Belikov, Aleksey V.
Vyatkin, Alexey D.
Leonov, Sergey V.
Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients
title Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients
title_full Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients
title_fullStr Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients
title_full_unstemmed Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients
title_short Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients
title_sort novel driver strength index highlights important cancer genes in tcga pancanatlas patients
topic Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9375969/
https://www.ncbi.nlm.nih.gov/pubmed/35975235
http://dx.doi.org/10.7717/peerj.13860
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