Detection of oncogenic and clinically actionable mutations in cancer genomes critically depends on variant calling tools
García-Prieto, Carlos A (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Martínez Jiménez, Francisco (Institute for Research in Biomedicine (IRB Barcelona))
Valencia, Alfonso (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Porta-Pardo, Eduard (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Data:	2022
Resum:	Motivation: The analysis of cancer genomes provides fundamental information about its etiology, the processes driving cell transformation or potential treatments. While researchers and clinicians are often only interested in the identification of oncogenic mutations, actionable variants or mutational signatures, the first crucial step in the analysis of any tumor genome is the identification of somatic variants in cancer cells (i. e. Those that have been acquired during their evolution). For that purpose, a wide range of computational tools have been developed in recent years to detect somatic mutations in sequencing data from tumor samples. While there have been some efforts to benchmark somatic variant calling tools and strategies, the extent to which variant calling decisions impact the results of downstream analyses of tumor genomes remains unknown. Results: Here, we quantify the impact of variant calling decisions by comparing the results obtained in three important analyses of cancer genomics data (identification of cancer driver genes, quantification of mutational signatures and detection of clinically actionable variants) when changing the somatic variant caller (MuSE, MuTect2, SomaticSniper and VarScan2) or the strategy to combine them (Consensus of two, Consensus of three and Union) across all 33 cancer types from The Cancer Genome Atlas. Our results show that variant calling decisions have a significant impact on these analyses, creating important differences that could even impact treatment decisions for some patients. Moreover, the Consensus of three calling strategy to combine the output of multiple variant calling tools, a very widely used strategy by the research community, can lead to the loss of some cancer driver genes and actionable mutations. Overall, our results highlight the limitations of widespread practices within the cancer genomics community and point to important differences in critical analyses of tumor sequencing data depending on variant calling, affecting even the identification of clinically actionable variants.
Nota:	Fundació Carreras
Nota:	This work was supported by the BSC-Lenovo Master Collaboration Agreement (2015) and the IBM-BSC Joint Study Agreement (JSA) on Precision Medicine under the IBM-BSC Deep Learning Center Agreement (to C.A.G.-P.). F.M.-J. was supported by funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [Grant Agreement No. 682398]. A.V. received support from Institució Catalana de Recerca i Estudis Avançats (ICREA). E.P.-P. received support by a La Caixa Junior Leader Fellowship [LCF/BQ/PI18/11630003] from Fundación La Caixa and a Ramon y Cajal fellowship from the Spanish Ministry of Science [RYC2019-026415-I]. The Barcelona Supercomputing Center and IRB Barcelona are recipients of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN; Government of Spain). The Josep Carreras Leukaemia Research Institute and IRB Barcelona are supported by CERCA (Generalitat de Catalunya). E.P-P. is supported by the Spanish Science Ministry (PID2019-107043R1-I00).
Nota:	The European Union?s Horizon 2020 research and innovation programme [Grant Agreement No. 682398]
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Carcinogenesis ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; Neoplasms ; Oncogenes ; Software
Publicat a:	Bioinformatics, Vol. 38 Núm. 12 (15 2022) , p. 3181-3191, ISSN 1367-4811

DOI: 10.1093/bioinformatics/btac306
PMID: 35512388

11 p, 1.3 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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