Optimizing panel-based tumor mutational burden (TMB) measurement.

Détails

ID Serval
serval:BIB_D315A8B5404A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Optimizing panel-based tumor mutational burden (TMB) measurement.
Périodique
Annals of oncology
Auteur(s)
Budczies J., Allgäuer M., Litchfield K., Rempel E., Christopoulos P., Kazdal D., Endris V., Thomas M., Fröhling S., Peters S., Swanton C., Schirmacher P., Stenzinger A.
ISSN
1569-8041 (Electronic)
ISSN-L
0923-7534
Statut éditorial
Publié
Date de publication
01/09/2019
Peer-reviewed
Oui
Volume
30
Numéro
9
Pages
1496-1506
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Panel sequencing based estimates of tumor mutational burden (psTMB) are increasingly replacing whole exome sequencing (WES) tumor mutational burden as predictive biomarker of immune checkpoint blockade (ICB).
A mathematical law describing psTMB variability was derived using a random mutation model and complemented by the contributions of non-randomly mutated real-world cancer genomes and intratumoral heterogeneity through simulations in publicly available datasets.
The coefficient of variation (CV) of psTMB decreased inversely proportional with the square root of the panel size and the square root of the TMB level. In silico simulations of all major commercially available panels in the TCGA pan-cancer cohort confirmed the validity of this mathematical law and demonstrated that the CV was 35% for TMB = 10 muts/Mbp for the largest panels of size 1.1-1.4 Mbp. Accordingly, misclassification rates (gold standard: WES) to separate 'TMBhigh' from 'TMBlow' using a cut-point of 199 mutations were 10%-12% in TCGA-LUAD and 17%-19% in TCGA-LUSC. A novel three-tier psTMB classification scheme which accounts for the likelihood of misclassification is proposed. Simulations in two WES datasets of immunotherapy treated patients revealed that small gene panels were poor predictors of ICB response. Moreover, we noted substantial intratumoral variance of psTMB scores in the TRACERx 100 cohort and identified indel burden as independent marker complementing missense mutation burden.
A universal mathematical law describes accuracy limitations inherent to psTMB, which result in substantial misclassification rates. This scenario can be controlled by two measures: (i) a panel design that is based on the mathematical law described in this article: halving the CV requires a fourfold increase in panel size, (ii) a novel three-tier TMB classification scheme. Moreover, inclusion of indel burden can complement TMB reports. This work has substantial implications for panel design, TMB testing, clinical trials and patient management.
Mots-clé
Biomarkers, Tumor/genetics, Humans, Mutation/genetics, Neoplasms/genetics, Neoplasms/pathology, Tumor Burden/genetics, Whole Exome Sequencing/statistics & numerical data, TMB, immune checkpoint blockade, immune-oncology, panel sequencing, tumor mutational burden
Pubmed
Web of science
Open Access
Oui
Création de la notice
18/07/2019 16:10
Dernière modification de la notice
20/06/2020 5:18
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