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Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

Authors :
Ley TJ
Miller C
Ding L
Raphael BJ
Mungall AJ
Robertson A
Hoadley K
Triche TJ Jr
Laird PW
Baty JD
Fulton LL
Fulton R
Heath SE
Kalicki-Veizer J
Kandoth C
Klco JM
Koboldt DC
Kanchi KL
Kulkarni S
Lamprecht TL
Larson DE
Lin L
Lu C
McLellan MD
McMichael JF
Payton J
Schmidt H
Spencer DH
Tomasson MH
Wallis JW
Wartman LD
Watson MA
Welch J
Wendl MC
Ally A
Balasundaram M
Birol I
Butterfield Y
Chiu R
Chu A
Chuah E
Chun HJ
Corbett R
Dhalla N
Guin R
He A
Hirst C
Hirst M
Holt RA
Jones S
Karsan A
Lee D
Li HI
Marra MA
Mayo M
Moore RA
Mungall K
Parker J
Pleasance E
Plettner P
Schein J
Stoll D
Swanson L
Tam A
Thiessen N
Varhol R
Wye N
Zhao Y
Gabriel S
Getz G
Sougnez C
Zou L
Leiserson MD
Vandin F
Wu HT
Applebaum F
Baylin SB
Akbani R
Broom BM
Chen K
Motter TC
Nguyen K
Weinstein JN
Zhang N
Ferguson ML
Adams C
Black A
Bowen J
Gastier-Foster J
Grossman T
Lichtenberg T
Wise L
Davidsen T
Demchok JA
Shaw KR
Sheth M
Sofia HJ
Yang L
Downing JR
Eley G
Source :
The New England journal of medicine [N Engl J Med] 2013 May 30; Vol. 368 (22), pp. 2059-74. Date of Electronic Publication: 2013 May 01.
Publication Year :
2013

Abstract

Background: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear.<br />Methods: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis.<br />Results: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories.<br />Conclusions: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).

Details

Language :
English
ISSN :
1533-4406
Volume :
368
Issue :
22
Database :
MEDLINE
Journal :
The New England journal of medicine
Publication Type :
Academic Journal
Accession number :
23634996
Full Text :
https://doi.org/10.1056/NEJMoa1301689