title: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia.
abstract: Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Sakaguchi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Mariko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Ayana
authors.initials: A
authors.lastname: Kon
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Xinan
authors.initials: X
authors.lastname: Wang
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Xu
authors.forename: Sayoko
authors.initials: S
authors.lastname: Doisaki
authors.forename: Asahito
authors.initials: A
authors.lastname: Hama
authors.forename: Koji
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Nao
authors.initials: N
authors.lastname: Yoshida
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D059472:Exome; D005260:Female; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053616:Janus Kinase 3 / Q000235:genetics*; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C425066:SETBP1 protein, human; D053616:Janus Kinase 3; D016283:Proto-Oncogene Proteins p21(ras)