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Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?

Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and vario...

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Autores principales: Noskova, Hana, Kyr, Michal, Pal, Karol, Merta, Tomas, Mudry, Peter, Polaskova, Kristyna, Ivkovic, Tina Catela, Adamcova, Sona, Hornakova, Tekla, Jezova, Marta, Kren, Leos, Sterba, Jaroslav, Slaby, Ondrej
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016876/
https://www.ncbi.nlm.nih.gov/pubmed/31963488
http://dx.doi.org/10.3390/cancers12010230
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author Noskova, Hana
Kyr, Michal
Pal, Karol
Merta, Tomas
Mudry, Peter
Polaskova, Kristyna
Ivkovic, Tina Catela
Adamcova, Sona
Hornakova, Tekla
Jezova, Marta
Kren, Leos
Sterba, Jaroslav
Slaby, Ondrej
author_facet Noskova, Hana
Kyr, Michal
Pal, Karol
Merta, Tomas
Mudry, Peter
Polaskova, Kristyna
Ivkovic, Tina Catela
Adamcova, Sona
Hornakova, Tekla
Jezova, Marta
Kren, Leos
Sterba, Jaroslav
Slaby, Ondrej
author_sort Noskova, Hana
collection PubMed
description Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and various settings of bioinformatic pipelines. In pediatric oncology, no study has been published describing this variability so far. Methods: In our study, we performed whole exome sequencing (WES, both germline and somatic) and calculated TMB in 106 patients with high-risk/recurrent pediatric solid tumors of 28 distinct cancer types. Subsequently, we used WES data for TMB calculation using an in silico approach simulating two The Food and Drug Administration (FDA)-approved/authorized comprehensive genomic panels for cancer. Results: We describe a strong correlation between WES-based and panel-based TMBs; however, we show that this high correlation is significantly affected by inclusion of only a few hypermutated cases. In the series of nine cases, we determined TMB in two sequentially collected tumor tissue specimens and observed an increase in TMB along with tumor progression. Furthermore, we evaluated the extent to which potential ICI indication could be affected by variability in techniques and bioinformatic pipelines used for TMB assessment. We confirmed that this technological variability could significantly affect ICI indication in pediatric cancer patients; however, this significance decreases with the increasing cut-off values. Conclusions: For the first time in pediatric oncology, we assessed the reliability of TMB estimation across multiple pediatric cancer types using real-life WES and in silico analysis of two major targeted gene panels and confirmed a significant technological variability to be introduced by different laboratory techniques and various settings of bioinformatic pipelines.
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spelling pubmed-70168762020-02-28 Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision? Noskova, Hana Kyr, Michal Pal, Karol Merta, Tomas Mudry, Peter Polaskova, Kristyna Ivkovic, Tina Catela Adamcova, Sona Hornakova, Tekla Jezova, Marta Kren, Leos Sterba, Jaroslav Slaby, Ondrej Cancers (Basel) Article Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and various settings of bioinformatic pipelines. In pediatric oncology, no study has been published describing this variability so far. Methods: In our study, we performed whole exome sequencing (WES, both germline and somatic) and calculated TMB in 106 patients with high-risk/recurrent pediatric solid tumors of 28 distinct cancer types. Subsequently, we used WES data for TMB calculation using an in silico approach simulating two The Food and Drug Administration (FDA)-approved/authorized comprehensive genomic panels for cancer. Results: We describe a strong correlation between WES-based and panel-based TMBs; however, we show that this high correlation is significantly affected by inclusion of only a few hypermutated cases. In the series of nine cases, we determined TMB in two sequentially collected tumor tissue specimens and observed an increase in TMB along with tumor progression. Furthermore, we evaluated the extent to which potential ICI indication could be affected by variability in techniques and bioinformatic pipelines used for TMB assessment. We confirmed that this technological variability could significantly affect ICI indication in pediatric cancer patients; however, this significance decreases with the increasing cut-off values. Conclusions: For the first time in pediatric oncology, we assessed the reliability of TMB estimation across multiple pediatric cancer types using real-life WES and in silico analysis of two major targeted gene panels and confirmed a significant technological variability to be introduced by different laboratory techniques and various settings of bioinformatic pipelines. MDPI 2020-01-17 /pmc/articles/PMC7016876/ /pubmed/31963488 http://dx.doi.org/10.3390/cancers12010230 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Noskova, Hana
Kyr, Michal
Pal, Karol
Merta, Tomas
Mudry, Peter
Polaskova, Kristyna
Ivkovic, Tina Catela
Adamcova, Sona
Hornakova, Tekla
Jezova, Marta
Kren, Leos
Sterba, Jaroslav
Slaby, Ondrej
Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?
title Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?
title_full Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?
title_fullStr Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?
title_full_unstemmed Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?
title_short Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?
title_sort assessment of tumor mutational burden in pediatric tumors by real-life whole-exome sequencing and in silico simulation of targeted gene panels: how the choice of method could affect the clinical decision?
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016876/
https://www.ncbi.nlm.nih.gov/pubmed/31963488
http://dx.doi.org/10.3390/cancers12010230
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