title: Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.
abstract: Activating mutations in tyrosine kinase (TK) genes (eg, FLT3 and KIT) are found in more than 30% of patients with de novo acute myeloid leukemia (AML); many groups have speculated that mutations in other TK genes may be present in the remaining 70%. We performed high-throughput resequencing of the kinase domains of 26 TK genes (11 receptor TK; 15 cytoplasmic TK) expressed in most AML patients using genomic DNA from the bone marrow (tumor) and matched skin biopsy samples ("germline") from 94 patients with de novo AML; sequence variants were validated in an additional 94 AML tumor samples (14.3 million base pairs of sequence were obtained and analyzed). We identified known somatic mutations in FLT3, KIT, and JAK2 TK genes at the expected frequencies and found 4 novel somatic mutations, JAK1(V623A), JAK1(T478S), DDR1(A803V), and NTRK1(S677N), once each in 4 respective patients of 188 tested. We also identified novel germline sequence changes encoding amino acid substitutions (ie, nonsynonymous changes) in 14 TK genes, including TYK2, which had the largest number of nonsynonymous sequence variants (11 total detected). Additional studies will be required to define the roles that these somatic and germline TK gene variants play in AML pathogenesis.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. tomasson@wustl.edu
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Richard
authors.initials: R
authors.lastname: Walgren
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kasai
authors.forename: Tracie
authors.initials: T
authors.lastname: Miner
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.forename: Olga
authors.initials: O
authors.lastname: Lubman
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: Jack
authors.initials: J
authors.lastname: Baty
authors.forename: Sharon
authors.initials: S
authors.lastname: Heath
authors.forename: William D
authors.initials: WD
authors.lastname: Shannon
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D011505:Protein-Tyrosine Kinases