Tumour mutational burden (TMB) is used to predict response to immunotherapies. Although several groups have proposed calculation methods for TMB, a clear consensus has not yet emerged. In this study, we explored TMB calculation approaches with a 586-gene cancer panel (1.75 Mb) benchmarked to TMB measured by whole-exome sequencing (WES), using 30 samples across a range of tumour types. We explored variant allelic fraction (VAF) cut-offs of 5% and 10%, population database filtering at 0.001, 0.0001 and 0.000025, as well as different combinations of synonymous, insertion/deletion and intronic (splice site) variants, as well as exclusion of hotspot mutations, and examined the effect on TMB correlation. Good correlation (Spearman, range 0.66–0.78) between WES and panel TMB was seen across all methods evaluated. Each method of TMB calculation evaluated showed good positive per cent agreement and negative per cent agreement using 10 mutations/Mb as a cut-off, suggesting that multiple TMB calculation approaches may yield comparable results.
- Biomarkers, Tumor
- Pathology, Molecular
- Diagnostic Techniques and Procedures
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Handling editor Runjan Chetty.
Contributors JP—conceptualisation, methodology, formal analysis and investigation. HX, SM and WZ—conceptualisation and investigation. DP and CF—conceptualisation, methodology and project administration. HF and MM—conceptualisation, methodology and writing (review and editing). SJH—conceptualisation, methodology, investigation and writing (original draft).
Funding This study was funded by Bristol Myers Squibb.
Competing interests SJH has received consulting fees from Opentrons Labworks and Loxo Oncology and honoraria from Illumina and Medscape.
Provenance and peer review Not commissioned; externally peer reviewed.
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