Abstract
BackgroundSomatic 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.MethodsSubjects 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.ResultsNGS 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.ConclusionsUse 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.
Highlights
Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers
next-generation sequencing (NGS)-based targeted DNA and RNA sequencing Panel design Ninety-nine genes associated with pediatric hematological malignancies, 237 genes associated with pediatric solid tumors, and 106 major fusion partner genes associated with cancer-related fusions are selected for the Children’s Hospital of Philadelphia (CHOP) Comprehensive Hematological Malignancy Panel (CHMP) and Comprehensive Solid Tumor Panel (CSTP)
Moving beyond overall trends in pediatric tumors, our results show that on a per-patient basis, comprehensive next-generation somatic tumor testing can be meaningfully incorporated into clinical care, as findings were clinically relevant in 78.7% of the patients tested in this cohort (Fig. 6 and Table 1)
Summary
Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Somatic genomic testing has become the standard of care in a variety of pediatric cancers for diagnostic refinement, risk stratification, and therapeutic approach, such as the incorporation of MCYN amplification, DNA ploidy, and segmental chromosomal aberrations in International Neuroblastoma Risk Group classification of neuroblastoma and the use of genetic profiling in World Health Organization (WHO) classification of central nervous system (CNS) malignancy [6,7,8,9,10]. Identification of somatic mutations, fusions, and other genomic aberrations has led to implementation of molecularly targeted therapies in several pediatric cancers, including Philadelphia chromosome positive (Ph (+)) and Ph-like acute lymphoblastic leukemia and ALK-mutated neuroblastoma [11, 12]. Clinical trials have begun to incorporate genomic profiling into selection of targeted agents [13]
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