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Abstract
The rapid decline in sequencing costs has allowed next-generation sequencing (NGS) assays, previously ubiquitous only in research laboratories, to begin making inroads into molecular diagnostics. Genotypic assays – DNA sequencing – include whole genome sequencing, whole exome sequencing, focused assays that target only a handful of genes. Phenotypic assays comprise a broader spectrum of options and can query a variety of epigenetic modifications of DNA (such as ChIP-seq, bisulfite sequencing, DNase-I hypersensitivity site-sequencing, Formaldehyde-Assisted Isolation of Regulatory Elements-sequencing, etc.) that regulate gene expression-related processes or gene expression (RNA-sequencing) itself. To date, the US FDA has only cleared 12 DNA-based companion diagnostic tests, all in cancer. Although challenges exist for NGS in companion diagnostics, the wide-ranging capabilities of NGS offer extraordinary opportunities for the development and implementation of NGS-based companion diagnostics to probe oncogenes, tumor suppressor genes and cancer-enabling genes.
Financial & competing interests disclosure
E Lin, J-B Fan and FS Ong are employees of Illumina, Inc. J Chien is funded by the University of Kansas Endowment Association and the Department of Defense Ovarian Cancer Research Program under award number W81XWH-10-1-0386. Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
The rapid decline in sequencing costs has allowed next-generation sequencing (NGS) platforms to be utilized in molecular diagnostics laboratories. As NGS technology becomes more widely adopted in the molecular diagnostic laboratories, one can expect NGS-based diagnostic assays and NGS companion diagnostics to become a central piece of routine healthcare management and genomic medicine.
Development of a knowledge base for clinical utilization of NGS genetic data for variant calling and annotation for clinical interpretation and results reporting is occurring on multiple fronts and includes refinement of current bioinformatics algorithms and pipelines as well as public and private initiatives to assist in the identification of and the development of a consensus on medically relevant genomic variants.
NGS is being utilized to understand and learn about ‘exceptional responders’, rare patients with unexpected exquisite sensitivity or durable responses to therapy. The study of exceptional responders represents a promising approach to better understand the mechanisms that underlie sensitivity to targeted anticancer therapies and adds to the knowledge base for clinical utilization of NGS data.
The ability for NGS to target a wide spectrum of mutations across a large number of genes/pathways could provide diagnostic information to identify focal amplifications responsible for drug resistance and corresponding targeted therapeutic agent(s) likely to be effective in treating patients as well as provide monitoring for acquired resistance to treatment.
NGS has been applied to studying circulating tumor cells and circulating tumor DNA and may be useful for future efforts in determining prognosis, monitoring response to therapy and rational selection of therapies in cancer patients.
The advent of adaptive model clinical trial models that include the ‘basket’ and ‘umbrella’ clinical trials provides an opportunity for co-development companion diagnostics and targeted therapies for precision cancer medicine.
Future effort in the development of companion diagnostics in cancer should focus on three areas: oncogenes, tumor suppressor genes and cancer-enabling genes. In the oncogene-related companion diagnostics, these efforts should focus not only on developing diagnostics that provide clinically actionable information on mutations and available drugs that target these mutations, but also on developing knowledge base of additional mutations that contribute to resistance to targeted therapies.