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N Engl J Med DOI:10.1056/NEJMoa1301689

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

Publication TypeJournal Article
Year of Publication2013
AuthorsLey, TJ, Miller, C, Ding, L, Raphael, BJ, Mungall, AJ, A Robertson, G, Hoadley, K, Triche, TJ, Laird, PW, Baty, JD, Fulton, LL, Fulton, R, Heath, SE, Kalicki-Veizer, J, Kandoth, C, Klco, JM, Koboldt, DC, Kanchi, K-L, 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, H-J, 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, MDM, Vandin, F, Wu, H-T, 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, KRMills, Sheth, M, Sofia, HJ, Yang, L, Downing, JR, Eley, G
Corporate AuthorsCancer Genome Atlas Research Network
JournalN Engl J Med
Volume368
Issue22
Pages2059-74
Date Published2013 05 30
ISSN1533-4406
KeywordsAdult, CpG Islands, DNA Methylation, Epigenomics, Female, Gene Expression, Gene Fusion, Genome, Human, Humans, Leukemia, Myeloid, Acute, Male, MicroRNAs, Middle Aged, Mutation, Sequence Analysis, DNA
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.

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.

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.

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.).

DOI10.1056/NEJMoa1301689
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23634996?dopt=Abstract

Alternate JournalN. Engl. J. Med.
PubMed ID23634996
PubMed Central IDPMC3767041
Grant ListU24CA143840 / CA / NCI NIH HHS / United States
P01CA101937 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
U24 CA143835 / CA / NCI NIH HHS / United States
U24 CA143866 / CA / NCI NIH HHS / United States
U24CA143858 / CA / NCI NIH HHS / United States
U24CA143882 / CA / NCI NIH HHS / United States
U24CA144025 / CA / NCI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
U24 CA143799 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 HG005690 / HG / NHGRI NIH HHS / United States
U24 CA144025 / CA / NCI NIH HHS / United States
U24CA143883 / CA / NCI NIH HHS / United States
U54HG003079 / HG / NHGRI NIH HHS / United States
U24 CA143840 / CA / NCI NIH HHS / United States
U24 CA143843 / CA / NCI NIH HHS / United States
U24CA143867 / CA / NCI NIH HHS / United States
U24CA143835 / CA / NCI NIH HHS / United States
U24 CA143858 / CA / NCI NIH HHS / United States
P30 CA091842 / CA / NCI NIH HHS / United States
U24CA143843 / CA / NCI NIH HHS / United States
U24 CA143848 / CA / NCI NIH HHS / United States
P01 CA101937 / CA / NCI NIH HHS / United States
U24CA143848 / CA / NCI NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
U24CA143799 / CA / NCI NIH HHS / United States
U24 CA143883 / CA / NCI NIH HHS / United States
R01 CA162086 / CA / NCI NIH HHS / United States
U24CA143866 / CA / NCI NIH HHS / United States
U24CA143845 / CA / NCI NIH HHS / United States
R01 CA083962 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States