The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Abstract

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children’s Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger–encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

NUP98‐BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy

“…NUP98‐BPTF was not identified in a large collection of AMKL specimens interrogated by next generation sequencing technologies where several gene fusions were uncovered (89 pediatric and 24 adult AMKL specimens) . NUP98‐BPTF was not reported among the gene fusions identified in a sampling of 197 pediatric AML interrogated by whole genome sequencing and supported by RNAseq or cytogenetic data . Nonetheless, out of 574 pediatric AML specimens interrogated by targeted approaches (e.g., cytogenetics, FISH, and selected RNAseq), 22 harbored a NUP98 rearrangement (3.8%) and one of them presented a complex karyotype with a t(11;17) (p15;q23) translocation, as detected in this AMLK case, involving an undefined NUP98 partner (CK#14) .…”

Acute myelogenous leukemia in adolescents and young adults

“…The frequency of cytogenetic subgroups of AML is associated with age. Increasing age is associated with a decrease in favorable cytogenetics and an increase in unfavorable cytogenetics (Table , Figure ) …”

“…Comprehensive comparison of AML molecular profiles across groups has shown marked differences in mutated genes, structural variants, and DNA methylation patterns that distinguish AML in infants, children, adolescents, and adults . Although mutational burden increased with age, the mutation rates of pediatric and young adult patients with AML are similar to those of adult patients with AML.…”

“…There is a higher prevalence of small sequence variants in older patients, whereas recurrent structural alterations, fusions, and focal copy number aberrations are more common in younger patients. Because of the overlap of genetic abnormalities associated with prognosis among these age‐defined groups, testing for these alterations is essential for the management of newly diagnosed patients with AML in any age group …”

Genomic testing in myeloid malignancy

“…Complicating the testing landscape, potentially preleukemic states such as clonal hematopoiesis of indeterminate potential (CHIP) (also referred to as age‐related clonal hematopoiesis), idiopathic cytopenia of undetermined significance (ICUS), and clonal cytopenias of undetermined significance (CCUS) have also been recently described . Pediatric AMLs have a different mutational landscape than adult leukemias, and so also require a different clinical approach . As well as screening patients at diagnosis, there are potential benefits to testing patients at remission and/or relapse.…”