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Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB

As tumor mutational burden (TMB) has been approved as a predictive biomarker for immune checkpoint inhibitors (ICIs), next-generation sequencing (NGS) TMB panels are being increasingly used clinically. However, only a few of them have been validated in clinical trials or authorized by administration...

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Autores principales: Sung, Meng-Ta, Wang, Yeh-Han, Li, Chien-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103036/
https://www.ncbi.nlm.nih.gov/pubmed/35563486
http://dx.doi.org/10.3390/ijms23095097
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author Sung, Meng-Ta
Wang, Yeh-Han
Li, Chien-Feng
author_facet Sung, Meng-Ta
Wang, Yeh-Han
Li, Chien-Feng
author_sort Sung, Meng-Ta
collection PubMed
description As tumor mutational burden (TMB) has been approved as a predictive biomarker for immune checkpoint inhibitors (ICIs), next-generation sequencing (NGS) TMB panels are being increasingly used clinically. However, only a few of them have been validated in clinical trials or authorized by administration. The harmonization and standardization of TMB panels are thus essential for clinical implementation. In this review, preanalytic, sequencing, bioinformatics and interpretative factors are summarized to provide a comprehensive picture of how the different factors affect the estimation of panel-based TMB. Among the factors, poor DNA quality, improper formalin fixation and residual germline variants after filtration may overestimate TMB, while low tumor purity may decrease the sensitivity of the TMB panel. In addition, a small panel size leads to more variability when comparing with true TMB values detected by whole-exome sequencing (WES). A panel covering a genomic region of more than 1Mb is more stable for harmonization and standardization. Because the TMB estimate reflects the sum of effects from multiple factors, deliberation based on laboratory and specimen quality, as well as clinical information, is essential for decision making.
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spelling pubmed-91030362022-05-14 Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB Sung, Meng-Ta Wang, Yeh-Han Li, Chien-Feng Int J Mol Sci Review As tumor mutational burden (TMB) has been approved as a predictive biomarker for immune checkpoint inhibitors (ICIs), next-generation sequencing (NGS) TMB panels are being increasingly used clinically. However, only a few of them have been validated in clinical trials or authorized by administration. The harmonization and standardization of TMB panels are thus essential for clinical implementation. In this review, preanalytic, sequencing, bioinformatics and interpretative factors are summarized to provide a comprehensive picture of how the different factors affect the estimation of panel-based TMB. Among the factors, poor DNA quality, improper formalin fixation and residual germline variants after filtration may overestimate TMB, while low tumor purity may decrease the sensitivity of the TMB panel. In addition, a small panel size leads to more variability when comparing with true TMB values detected by whole-exome sequencing (WES). A panel covering a genomic region of more than 1Mb is more stable for harmonization and standardization. Because the TMB estimate reflects the sum of effects from multiple factors, deliberation based on laboratory and specimen quality, as well as clinical information, is essential for decision making. MDPI 2022-05-03 /pmc/articles/PMC9103036/ /pubmed/35563486 http://dx.doi.org/10.3390/ijms23095097 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sung, Meng-Ta
Wang, Yeh-Han
Li, Chien-Feng
Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB
title Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB
title_full Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB
title_fullStr Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB
title_full_unstemmed Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB
title_short Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB
title_sort open the technical black box of tumor mutational burden (tmb): factors affecting harmonization and standardization of panel-based tmb
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103036/
https://www.ncbi.nlm.nih.gov/pubmed/35563486
http://dx.doi.org/10.3390/ijms23095097
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