Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.
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.
Tomasson
Michael H
MH
Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. tomasson@wustl.edu
Xiang
Zhifu
Z
Walgren
Richard
R
Zhao
Yu
Y
Kasai
Yumi
Y
Miner
Tracie
T
Ries
Rhonda E
RE
Lubman
Olga
O
Fremont
Daved H
DH
McLellan
Michael D
MD
Payton
Jacqueline E
JE
Westervelt
Peter
P
DiPersio
John F
JF
Link
Daniel C
DC
Walter
Matthew J
MJ
Graubert
Timothy A
TA
Watson
Mark
M
Baty
Jack
J
Heath
Sharon
S
Shannon
William D
WD
Nagarajan
Rakesh
R
Bloomfield
Clara D
CD
Mardis
Elaine R
ER
Wilson
Richard K
RK
Ley
Timothy J
TJ
D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*
D011505:Protein-Tyrosine Kinases