Abstract
Timely and accurate identification of molecular alterations in solid tumors is essential for proper management of patients with advanced cancers. This has created a need for rapid, scalable comprehensive genomic profiling (CGP) systems that detect an increasing number of therapeutically-relevant variant types and molecular signatures. In this study, we assessed the analytical performance of the TruSight Oncology 500 High-Throughput assay for detection of somatic alterations from formalin-fixed paraffin-embedded tissue specimens. In parallel, we developed supporting software and automated sample preparation systems designed to process up to 70 clinical samples in a single NovaSeq 6000TM sequencing run with a turnaround time of <7 days from specimen receipt to report. The results demonstrate that the scalable assay accurately and reproducibly detects small variants, copy number alterations, microsatellite instability (MSI) and tumor mutational burden (TMB) from 40ng DNA, and multiple gene fusions, including known and unknown partners and splice variants from 20ng RNA. 717 tumor samples and reference materials with previously known alterations in 96 cancer-related genes were sequenced to evaluate assay performance. All variant classes were reliably detected at consistent and reportable variant allele percentages with >99% overall accuracy and precision. Our results demonstrate that the high-throughput CGP assay is a reliable method for accurate detection of molecular alterations in support of precision therapeutics in oncology. The supporting systems and scalable workflow allow for efficient interpretation and prompt reporting of hundreds of patient cancer genomes per week with excellent analytical performance.
Highlights
Next-generation sequencing (NGS) technologies for comprehensive genomic profiling (CGP) of solid tumor samples have been established as standard of care in the clinical setting for the management of patients with advanced cancers [1,2,3,4,5]
We present our initial results of the Illumina TruSight Oncology 500 (TSO500TM) High-Throughput assay as a scalable CGP method to reliably detect and deliver clinically useful biomarker information in support of precision therapeutics in oncology
Comprehensive genomic profiling using targeted NGS is a powerful tool for the detection of genomic alterations and other tumor biomarkers that support precision medicine
Summary
Next-generation sequencing (NGS) technologies for comprehensive genomic profiling (CGP) of solid tumor samples have been established as standard of care in the clinical setting for the management of patients with advanced cancers [1,2,3,4,5]. Larger targeted panels that identify novel and emerging biomarkers have been developed to accommodate recent FDA approvals for TMB and MSI as genomic biomarkers of response to immune checkpoint inhibitors (ICI) in addition to the growing list of markers needed to select patients for novel targeted therapies [20,21,22,23,24,25,26].The initial connection between high TMB and response to ICI was achieved through whole exome sequencing (WES) studies of tumor and paired normal tissues. Sequencing of genomic instability for MSI, and homologous recombination deficiency (HRD), can be simultaneously accomplished with larger targeted panels using a tumor-only approach, thereby eliminating the need for matched normal tissue [31, 32]
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