Abstract
IntroductionThe identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology 500 (TSO500) panel and compared these to whole-genome sequencing (WGS).MethodsCancer samples derived from formalin-fixed material were profiled on the TSO500 panel, sequenced on an Illumina NextSeq 500 instrument and processed through the TSO500 Docker pipeline. Either FASTQ files (PierianDx) or vcf files (OncoKDM) were processed to understand clinical actionability.ResultsIn total, 108 samples (a mixture of colorectal, lung, oesophageal and control samples) were processed via the DNA panel. There was good correlation between TMB, single-nucleotide variants (SNVs), indels and copy-number variations as predicted by TSO500 and WGS (R2 > 0.9) and good reproducibility, with less than 5% variability between repeated controls. For the RNA panel, 13 samples were processed, with all known fusions observed via orthogonal techniques. For clinical actionability, 72 tier 1 variants and 297 tier 2 variants were detected, with clinical trials identified for all patients.ConclusionsThe TSO500 assay accurately measures TMB, microsatellite instability, SNVs, indels, copy-number/structural variation and gene fusions when compared to WGS and orthogonal technologies. Coupled with a clinical annotation pipeline, this provides a powerful methodology for identification of clinically actionable variants.Electronic supplementary materialThe online version of this article (10.1007/s40291-020-00462-x) contains supplementary material, which is available to authorized users.
Highlights
The identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this
We utilised the TruSight Oncology 500 (TSO500) assay in order to understand its utility and accuracy in determining both the TMB and druggable mutation calls in cancer
The assay was designed in its first iteration to measure TMB as a surrogate marker for response to anti–PD-1 immunotherapy, as multiple studies have shown a correlation between TMB and response to this type of therapy [8, 13]
Summary
The identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology 500 (TSO500) panel and compared these to whole-genome sequencing (WGS). Conclusions The TSO500 assay accurately measures TMB, microsatellite instability, SNVs, indels, copy-number/structural variation and gene fusions when compared to WGS and orthogonal technologies. The Illumina TruSight Oncology 500 assay provides an option to detect relevant cancer gene mutations and fusions. These variants can be annotated with clinical interpretation software for ease of clinical interpretation protein 1 (PD-1) and programmed death-ligand 1 (PDL1) receptors using therapeutic monoclonal antibodies [1] can unmask cancer to the immune system, facilitating its immune-mediated destruction. Based on the CHECKMATE trials, the suggested TMB threshold is greater than 10 mutations (mut)/Mb, based on the objective response rates of the tumours in these studies not improving much beyond this threshold
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
