Recurring mutations found by sequencing an acute myeloid leukemia genome.
BACKGROUND
The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.


METHODS
We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome.


RESULTS
We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis.


CONCLUSIONS
By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.
Mardis
Elaine R
ER
Department of Genetics, Washington University, St. Louis, MO 63110, USA.
Ding
Li
L
Dooling
David J
DJ
Larson
David E
DE
McLellan
Michael D
MD
Chen
Ken
K
Koboldt
Daniel C
DC
Fulton
Robert S
RS
Delehaunty
Kim D
KD
McGrath
Sean D
SD
Fulton
Lucinda A
LA
Locke
Devin P
DP
Magrini
Vincent J
VJ
Abbott
Rachel M
RM
Vickery
Tammi L
TL
Reed
Jerry S
JS
Robinson
Jody S
JS
Wylie
Todd
T
Smith
Scott M
SM
Carmichael
Lynn
L
Eldred
James M
JM
Harris
Christopher C
CC
Walker
Jason
J
Peck
Joshua B
JB
Du
Feiyu
F
Dukes
Adam F
AF
Sanderson
Gabriel E
GE
Brummett
Anthony M
AM
Clark
Eric
E
McMichael
Joshua F
JF
Meyer
Rick J
RJ
Schindler
Jonathan K
JK
Pohl
Craig S
CS
Wallis
John W
JW
Shi
Xiaoqi
X
Lin
Ling
L
Schmidt
Heather
H
Tang
Yuzhu
Y
Haipek
Carrie
C
Wiechert
Madeline E
ME
Ivy
Jolynda V
JV
Kalicki
Joelle
J
Elliott
Glendoria
G
Ries
Rhonda E
RE
Payton
Jacqueline E
JE
Westervelt
Peter
P
Tomasson
Michael H
MH
Watson
Mark A
MA
Baty
Jack
J
Heath
Sharon
S
Shannon
William D
WD
Nagarajan
Rakesh
R
Link
Daniel C
DC
Walter
Matthew J
MJ
Graubert
Timothy A
TA
DiPersio
John F
JF
Wilson
Richard K
RK
Ley
Timothy J
TJ
D000328:Adult; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D015894:Genome, Human; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D017354:Point Mutation; D017422:Sequence Analysis, DNA / Q000379:methods
C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human