Clinical Impact of Genomic Information in Pediatric Leukemia

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.

Utilization of Genomic Tumor Profiling in Pediatric Liquid Tumors: A Clinical Series

“…As previously mentioned, the Muscleblind Like Splicing Regulator ( MBNL1 ), Zinc Finger E-Box Binding Homeobox 2 ( ZEB2) , MLL gene, and E74-like factor 1 ( ELF1 ) genes are disproportionately prevalent in pediatric AML tumors in comparison to adult AML tumors [ 9 , 26 ]. Further, mutations in DNA methyltransferase 3 alpha ( DNMT3A ) and tumor protein 53 ( TP53 ) genes, which drive AML in adult patients, are absent in most pediatric AML cases [ 10 , 11 , 12 ].…”

“…Furthermore, expanded testing for pediatric leukemias and lymphomas at diagnosis may allow for the incorporation of targeted therapies early on, as opposed to high-dose chemotherapies that result in short- and long-term toxicities. Current recommendations, while suggesting the importance of molecular profiling in liquid tumors, do not recommend standard profiling for at least a subset of tumors, unlike in adult patients [ 12 , 13 ]. However, our experience and other studies have demonstrated the feasibility of incorporating sequencing in pediatric cancer care [ 36 , 44 ].…”

“…The College of American Pathologists and the American Society of Hematology recently acknowledged that pediatric ALL is more heterogeneous than previously understood, especially for relapsing and refractory patients. As such, the bodies recommended the use of molecular profiling in identifying biomarkers, prognostic factors, and genetic abnormalities for therapeutic targets [ 12 , 13 ]. There remains, however, limited consensus on how and when to use molecular profiling to guide treatment options for pediatric liquid tumors.…”

Immunoglobulin Heavy Chain High-Throughput Sequencing in Pediatric B-Precursor Acute Lymphoblastic Leukemia: Is the Clonality of the Disease at Diagnosis Related to Its Prognosis?

“…One possible explanation for this is the relatively small number of cases investigated. Although this study constitutes one of the biggest cohorts on IgH HTS at diagnosis, the sample size would not have allowed enough statistical power to analyze the association between clonal complexity and EFS or other described prognostic factors of pediatric leukemia, which is indeed a very heterogeneous disease with many prognostic factors present only in small subsets of patients, as, for example, genetic abnormalities ( 52 , 53 ). Furthermore, only patients with IgH recombinations were included in this study and we did not investigate the association between the absence of IgH recombination (which stipulated an exclusion from our cohort) and belonging to a particular group of risk.…”

Application of Next Generation Sequencing in Laboratory Medicine

“…NGS has a wide spectrum of applications in laboratory medicine and has become an integrated part of precision medicine. The technology has been widely used in diagnosis, prognosis, and therapy selection for constitutional disorders, oncology, and infectious diseases [3][4][5]. Concurrently, an increasing amount of well curated clinical, genetic, and genomic data is being generated by NGS, further driving the development of precision medicine [6].…”