Clinical utility of custom-designed NGS panel testing in pediatric tumors

Abstract

Background Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers. Methods Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed. Results NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration. Conclusions Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients. Electronic supplementary material The online version of this article (10.1186/s13073-019-0644-8) contains supplementary material, which is available to authorized users.

Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL

“…The Ph-like TVA1 cell line was initially created as a childhood Ph-like ALL patient-derived xenograft (PDX) model in immunocompromised mice and subsequently immortalized via in vitro culture (52). Archer fusionplex testing and next-generation sequencing of some cell lines and PDX models were performed at the CHOP Division of Genomic Diagnostics clinical core facility as previously described (64). The Ph-like kinase-activated gene expression signature was confirmed by a validated clinical low-density microarray analysis in relevant ALL cell lines and PDX models as previously described (6,20,65).…”

Pediatric low-grade glioma in the era of molecular diagnostics

“…In recent years, the use of next-generation sequencing (NGS) platforms for the molecular characterization of solid tumors has gained significant popularity [113,175,209]. These platforms range from approximately 300-500 gene targets (or more) and often include most of those altered in pLGG.…”

Strong concordance between RNA structural and single nucleotide variants identified via next generation sequencing techniques in primary pediatric leukemia and patient-derived xenograft samples

“…They leveraged ArcherDx Fu-sionPlex technology (identical to our approach) to identify these cases. Additionally, several recent studies have demonstrated the use of AMP technology (ArcherDx) for identifying rare and complex structural variants in pediatric cancers [32,33]. Taken together, advanced sequencing techniques are required to accurately detect and annotate complex StVs that are commonly associated with pediatric leukemias.…”