Journal Article

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

Noort, Sanne, Liu, Yanling, Ries, Rhonda E, Ma, Xiaotu, Lim, Emilia L, Bolouri, Hamid, Triche, Timothy, Marra, Marco A, Salhia, Bodour, Mungall, Andrew J, Zhang, Jinghui, Hermida, Leandro C, Davidsen, Tanja M, Gamis, Alan S, Moore, Richard, Farrar, Jason E, Zwaan, Christian Michel, Liu, Yu, Alonzo, Todd A, Piccolo, Stephen R, Meshinchi, Soheil, Ma, Yussanne, Kolb, E Anders, Capone, Stephen, Smith, Malcolm A, Gerhard, Daniela S, Guidry Auvil, Jaime M., Gesuwan, Patee, Ramsingh, Giridharan

2018

Overview

A comprehensive molecular analysis of almost 1,000 pediatric subjects with acute myeloid leukemia (AML) uncovers widespread differences in pediatric AML as compared to adult AML, including a higher frequency of structural variants and different mutational patterns and epigenetic signatures. Future studies are needed to characterize the functional relevance of these alterations and to explore age-tailored therapies to improve disease control in younger patients. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/23 / 38/39 / 38/77 / 38/91 / 631/67/1857 / 631/67/1990/283/1897 / 631/67/2332 / 631/67/69 / 692/699/1541/1990/283/1897 / Acute myelocytic leukemia / Acute myeloid leukemia / Adults / Age / Age groups / Biomedicine / Cancer Research / Cell interactions / Child / Childhood / Children / Chromosome Aberrations / Clinical trials / Comparative analysis / CpG islands / Deoxyribonucleic acid / Disease control / DNA / DNA fingerprinting / DNA Methylation / DNA sequencing / Epigenetics / Gene mutation / Gene sequencing / Genes / Genetic aspects / Genomes / Health aspects / Humans / Immune system / Infectious Diseases / K-Ras protein / Kinases / Leukemia / Leukemia, Myeloid, Acute - genetics / Metabolic Diseases / Methylation / MicroRNAs / miRNA / Molecular Medicine / mRNA / Mutation / Myc protein / Myeloid leukemia / Neurosciences / p53 Protein / Pediatrics / Physiological aspects / Polycomb group proteins / Proteins / Remission (Medicine) / resource / Ribonucleic acid / RNA / Signaling / Transcriptome / Wnt protein / Zinc finger proteins