Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. Whole Exome Sequencing (WES) allows comprehensive measurement of TMB and is considered the gold standard. However, to date WES remains confined to research settings, due to high cost of the large genomic space sequenced. In the clinical setting, instead, targeted enrichment panels (gene panels) of various genomic sizes are emerging as the routine technology for TMB assessment. This stimulated the development of various methods for panel-based TMB quantification, and prompted the multiplication of studies assessing whether TMB can be confidently estimated from the smaller genomic space sampled by gene panels. In this review, we inventory the collection of available gene panels tested for this purpose, illustrating their technical specifications and describing their accuracy and clinical value in TMB assessment. Moreover, we highlight how various experimental, platform-related or methodological variables, as well as bioinformatic pipelines, influence panel-based TMB quantification. The lack of harmonization in panel-based TMB quantification, of adequate methods to convert TMB estimates across different panels and of robust predictive cutoffs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice. This overview on the heterogeneous landscape of panel-based TMB quantification aims at providing a context to discuss common standards and illustrates the strong need of further validation and consolidation studies for the clinical interpretation of panel-based TMB values.

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges / L. Fancello, S. Gandini, P.G. Pelicci, L. Mazzarella. - In: JOURNAL FOR IMMUNOTHERAPY OF CANCER. - ISSN 2051-1426. - 7:1(2019), pp. 183.1-183.13. [10.1186/s40425-019-0647-4]

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

P.G. Pelicci;L. Mazzarella
Ultimo
2019

Abstract

Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. Whole Exome Sequencing (WES) allows comprehensive measurement of TMB and is considered the gold standard. However, to date WES remains confined to research settings, due to high cost of the large genomic space sequenced. In the clinical setting, instead, targeted enrichment panels (gene panels) of various genomic sizes are emerging as the routine technology for TMB assessment. This stimulated the development of various methods for panel-based TMB quantification, and prompted the multiplication of studies assessing whether TMB can be confidently estimated from the smaller genomic space sampled by gene panels. In this review, we inventory the collection of available gene panels tested for this purpose, illustrating their technical specifications and describing their accuracy and clinical value in TMB assessment. Moreover, we highlight how various experimental, platform-related or methodological variables, as well as bioinformatic pipelines, influence panel-based TMB quantification. The lack of harmonization in panel-based TMB quantification, of adequate methods to convert TMB estimates across different panels and of robust predictive cutoffs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice. This overview on the heterogeneous landscape of panel-based TMB quantification aims at providing a context to discuss common standards and illustrates the strong need of further validation and consolidation studies for the clinical interpretation of panel-based TMB values.
Gene panels; Immunotherapy; TMB; Targeted enrichment sequencing; Tumor mutational burden; Biomarkers, Tumor; Humans; Immunotherapy; Mutation; Neoplasms
Settore MED/04 - Patologia Generale
2019
Article (author)
File in questo prodotto:
File Dimensione Formato  
183.full.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.18 MB
Formato Adobe PDF
1.18 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/930360
Citazioni
  • ???jsp.display-item.citation.pmc??? 154
  • Scopus 223
  • ???jsp.display-item.citation.isi??? 211
social impact