Abstract
Pediatric leukemia remains a significant contributor to childhood lethality rates. However, recent development of new technologies including next-generation sequencing (NGS) has increased our understanding of the biological and genetic underpinnings of leukemia, resulting in novel diagnostic and treatment paradigms. The most prevalent pediatric leukemias include B-cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). These leukemias are highly heterogeneous, both clinically and genetically. There are multiple genetic subgroups defined by the World Health Organization, each with distinct clinical management. Clinical laboratories have started adopting genomic testing strategies to include high-throughput sequencing assays which, together with conventional cytogenetic techniques, enable optimal patient care. This review summarizes genetic and genomic techniques used in clinical laboratories to support management of pediatric leukemia, highlighting technical, biological, and clinical advances. We illustrate clinical utilities of comprehensive genomic evaluation of leukemia genomes through clinical case examples, which includes the interrogations of hundreds of genes and multiple mutation mechanisms using NGS technologies. Finally, we provide a future perspective on clinical genomics and precision medicine.
Highlights
Leukemia accounts for 30% of all childhood malignancies in the United States [1, 2]
This review summarizes genetic and genomic techniques used in clinical laboratories to support management of pediatric leukemia, highlighting technical, biological, and clinical advances
The patient had previously tested negative by conventional technologies; we identified a PAX5–JAK2 fusion (Figure 1A) along with biallelic loss of TP53 function
Summary
Leukemia accounts for 30% of all childhood malignancies in the United States [1, 2]. Advances in the biological understanding of leukemogenesis and improved treatment options have significantly increased survival rates, with childhood mortality rates decreasing nearly fourfold from 1975 to 2016 [1,2,3]. The repertoire of clinically significant genomic mutations in hematological malignancies includes a wide variety of alterations These include single-nucleotide variants (SNVs) leading to missense or nonsense amino acid changes; splice site substitutions affecting normal RNA processing; small deletions, duplications, insertions, or a combination of these commonly referred to as indels; copy number variations (CNVs); and large structural variations, disrupting the function of the genes involved or resulting in new fusion genes. We have developed a NGS-based comprehensive hematological cancer panel to profile genomic alterations of all leukemia patients at diagnosis and at relapse This panel is designed to interrogate SNVs, indels, CNVs/LOH in more than 100 genes, and both known and novel fusions associated with 106 major fusion partners. This thorough approach has required extensive investment in infrastructure, equipment, information technology, data storage, and skilled personnel, the enhanced analysis has clearly impacted care of pediatric leukemia patients
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