TY - JOUR
T1 - The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions
AU - Bolouri, Hamid
AU - Farrar, Jason E.
AU - Triche, Timothy
AU - Ries, Rhonda E.
AU - Lim, Emilia L.
AU - Alonzo, Todd A.
AU - Ma, Yussanne
AU - Moore, Richard
AU - Mungall, Andrew J.
AU - Marra, Marco A.
AU - Zhang, Jinghui
AU - Ma, Xiaotu
AU - Liu, Yu
AU - Liu, Yanling
AU - Auvil, Jaime M.Guidry
AU - Davidsen, Tanja M.
AU - Gesuwan, Patee
AU - Hermida, Leandro C.
AU - Salhia, Bodour
AU - Capone, Stephen
AU - Ramsingh, Giridharan
AU - Zwaan, Christian Michel
AU - Noort, Sanne
AU - Piccolo, Stephen R.
AU - Kolb, E. Anders
AU - Gamis, Alan S.
AU - Smith, Malcolm A.
AU - Gerhard, Daniela S.
AU - Meshinchi, Soheil
N1 - Publisher Copyright:
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040325975&partnerID=8YFLogxK
U2 - 10.1038/nm.4439
DO - 10.1038/nm.4439
M3 - Article
C2 - 29227476
AN - SCOPUS:85040325975
SN - 1078-8956
VL - 24
SP - 103
EP - 112
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -