![]() 5 Conversely, rearrangements involving the KMT2A gene (formerly MLL) on chromosome 11q23 are associated with higher levels of residual disease at the end of induction, which when present, are associated with inferior outcomes. ETV6-RUNX1 fusions are present in 20% to 25% of pediatric B-ALL cases, and they are associated with an excellent outcome. The most common translocation in pediatric B-ALL is t(12 21), which results in the ETV6-RUNX1 fusion gene. In addition to aneuploidy, a number of chromosomal translocations and other structural chromosomal aberrations with prognostic impact are common in B-ALL. Somatic mutations enriched at relapse >50% TP53 mutations in low-hypodiploid B-ALL are germ line germ-line TP53 mutations associated with poor EFS/OS and increased risk for second malignancyĮnzyme involved in nucleoside analog metabolism gain of function mutations likely lead to decreased sensitivity to antimetabolite therapyĪt diagnosis incidence varies by type of B-ALL ∼50 of relapsed B-ALLĪssociated with glucocorticoid resistance ![]() Unfavorable improved with intensification of therapyĩ0 low-hypodiploid B-ALL (32-39 chromosomes) ![]() Hypomethylating agents DOT1L inhibitors Menin-KMT2A protein-protein interaction inhibitors PRMT5 inhibitors LSD1 inhibitors Unfavorable noninfant improved with intensification of therapy infant KMT2A-r dismal outcome regardless of therapy intensity Some consortia consider specific trisomies, +4 and +10 considered favorable by COG Hyperdiploidy DNA Index >1.16 or >50 chromosomes This has facilitated the translation of genomic profiling studies of large, well-annotated cohorts of pediatric patients with hematologic malignancies being uniformly treated on clinical trials. Recent advances have facilitated routine performance of next generation sequencing assays in clinical environments. As broadly defined, precision medicine includes precise assignment of patients to risk-based therapy, identification of targetable genetic lesions, and individualization of chemotherapy dosing. These challenges have fueled the pursuit of “precision medicine” for the care of children with hematologic malignancies. Additionally, standard chemotherapy can be associated with a high burden of toxicity, both immediately and lifelong, for childhood cancer survivors. However, certain diseases and specific subsets of patients still have suboptimal outcomes with current standard of care treatment. The outcomes of children with most hematologic malignancies have steadily improved over recent decades. Here, we review emerging genomic data germane to pediatric hematologic malignancies. Importantly, the identification of germ-line mutations and variants with possible implications for members of the patient’s family raises challenging ethical questions. Although incredibly promising, many questions remain, including the biologic significance of identified genetic lesions and their clinical implications in the context of contemporary therapy. Additionally, a number of recent discoveries may positively impact the care of pediatric leukemia patients through refinement of risk stratification, identification of targetable genetic lesions, and determination of risk for therapy-related toxicity. The findings have deepened our understanding of the biology of many childhood leukemias. These efforts have defined the mutational landscape of a number of leukemia subtypes and also identified germ-line genetic variants biologically and clinically relevant to pediatric leukemias. Pediatric hematologic malignancies have been no exception, with a multitude of next generation sequencing studies conducted on large cohorts of patients in recent years. Over the past decade, there has been exponential growth in the number of genome sequencing studies performed across a spectrum of human diseases as sequencing technologies and analytic pipelines improve and costs decline.
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