Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

More than 25% of patients with AML carry no mutations in genes known to be associated with leukemia. Analyses of genomes, transcriptomes, and methylomes of AML samples implicate mutations in cytogenetically normal AML and provide insight into the relationships among causative genes. The molecular pa...

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Published inThe New England journal of medicine Vol. 368; no. 22; pp. 2059 - 2074
Main Authors Ley, Timothy J, Miller, Christopher, Ding, Li, Raphael, Benjamin J, Mungall, Andrew J, Robertson, A Gordon, Hoadley, Katherine, Triche, Jr, Timothy J, Laird, Peter W, Baty, Jack D, Fulton, Lucinda L, Fulton, Robert, Heath, Sharon E, Kalicki-Veizer, Joelle, Kandoth, Cyriac, Klco, Jeffery M, Koboldt, Daniel C, Kanchi, Krishna-Latha, Kulkarni, Shashikant, Lamprecht, Tamara L, Larson, David E, Lin, Ling, Lu, Charles, McLellan, Michael D, McMichael, Joshua F, Payton, Jacqueline, Schmidt, Heather, Spencer, David H, Tomasson, Michael H, Wallis, John W, Wartman, Lukas D, Watson, Mark A, Welch, John, Wendl, Michael C, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron, Chiu, Readman, Chu, Andy, Chuah, Eric, Chun, Hye-Jung, Corbett, Richard, Dhalla, Noreen, Guin, Ranabir, He, An, Hirst, Carrie, Hirst, Martin, Holt, Robert A, Jones, Steven, Karsan, Aly, Lee, Darlene, Li, Haiyan I, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Karen, Parker, Jeremy, Pleasance, Erin, Plettner, Patrick, Schein, Jacquie, Stoll, Dominik, Swanson, Lucas, Tam, Angela, Thiessen, Nina, Varhol, Richard, Wye, Natasja, Zhao, Yongjun, Gabriel, Stacey, Getz, Gad, Sougnez, Carrie, Zou, Lihua, Leiserson, Mark D M, Vandin, Fabio, Wu, Hsin-Ta, Applebaum, Frederick, Baylin, Stephen B, Akbani, Rehan, Broom, Bradley M, Chen, Ken, Motter, Thomas C, Nguyen, Khanh, Weinstein, John N, Zhang, Nianziang, Ferguson, Martin L, Adams, Christopher, Black, Aaron, Bowen, Jay, Gastier-Foster, Julie, Grossman, Thomas, Lichtenberg, Tara, Wise, Lisa, Davidsen, Tanja, Demchok, John A, Shaw, Kenna R Mills, Sheth, Margi, Sofia, Heidi J, Yang, Liming, Downing, James R, Eley, Greg
Format Journal Article
LanguageEnglish
Published Waltham, MA Massachusetts Medical Society 30.05.2013
Subjects
Online AccessGet full text
ISSN0028-4793
1533-4406
1533-4406
DOI10.1056/NEJMoa1301689

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Abstract More than 25% of patients with AML carry no mutations in genes known to be associated with leukemia. Analyses of genomes, transcriptomes, and methylomes of AML samples implicate mutations in cytogenetically normal AML and provide insight into the relationships among causative genes. The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades. Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (i.e., somatic mutations) have an essential role in pathogenesis. 1 , 2 However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays 3 – 5 (see Glossary). Targeted sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2 . 6 – 8 Massively parallel . . .
AbstractList More than 25% of patients with AML carry no mutations in genes known to be associated with leukemia. Analyses of genomes, transcriptomes, and methylomes of AML samples implicate mutations in cytogenetically normal AML and provide insight into the relationships among causative genes. The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades. Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (i.e., somatic mutations) have an essential role in pathogenesis. 1 , 2 However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays 3 – 5 (see Glossary). Targeted sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2 . 6 – 8 Massively parallel . . .
BackgroundMany 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.MethodsWe 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.ResultsAML 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.ConclusionsWe 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.)
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.BACKGROUNDMany 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.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.METHODSWe 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.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.RESULTSAML 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.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.).CONCLUSIONSWe 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.).
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. 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. 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. 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.).
Author Tomasson, Michael H
Holt, Robert A
Parker, Jeremy
Nguyen, Khanh
Zhang, Nianziang
Chun, Hye-Jung
Moore, Richard A
Hirst, Carrie
Kalicki-Veizer, Joelle
Guin, Ranabir
Miller, Christopher
Zhao, Yongjun
Motter, Thomas C
Kanchi, Krishna-Latha
Grossman, Thomas
Adams, Christopher
Wise, Lisa
Raphael, Benjamin J
Weinstein, John N
Schein, Jacquie
Robertson, A Gordon
Varhol, Richard
Watson, Mark A
Baylin, Stephen B
Kulkarni, Shashikant
Corbett, Richard
Birol, Inanc
Mayo, Michael
Broom, Bradley M
Tam, Angela
Jones, Steven
Shaw, Kenna R Mills
Chu, Andy
Ley, Timothy J
Li, Haiyan I
Koboldt, Daniel C
Black, Aaron
Demchok, John A
Swanson, Lucas
Bowen, Jay
Chuah, Eric
Balasundaram, Miruna
Hirst, Martin
Davidsen, Tanja
Yang, Liming
Larson, David E
Ferguson, Martin L
Klco, Jeffery M
Triche, Jr, Timothy J
Kandoth, Cyriac
Plettner, Patrick
Zou, Lihua
Chen, Ken
Schmidt, Heather
Lee, Darlene
Heath, Sharon E
Hoadley, Katherine
Eley, Greg
Lamprecht, Tamara L
Wu, Hsin-Ta
Karsan, Aly
Stoll, Dominik
Ding, Li
Baty, Jack D
Fulton, Lucinda L
Vandin, Fabio
Downing, James R
Wye, Natasj
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Copyright Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2014 INIST-CNRS
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Issue 22
Keywords Human
Medicine
Acute myelogenous leukemia
Genomics
Adult
Malignant hemopathy
Genome
De novo
Cancer
Language English
License CC BY 4.0
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content type line 14
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The members of the Cancer Genome Atlas Research Network are listed in the Appendix.
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Snippet More than 25% of patients with AML carry no mutations in genes known to be associated with leukemia. Analyses of genomes, transcriptomes, and methylomes of AML...
Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and...
BackgroundMany mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and...
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StartPage 2059
SubjectTerms Acute myeloid leukemia
Adult
Algorithms
Biological and medical sciences
Chromatin
Classification
Cohesin
Consolidation
CpG Islands
DNA Methylation
DNA sequencing
Epigenetics
Epigenomics
Female
Gene Expression
Gene Fusion
General aspects
Genome, Human
Genomes
Hematologic and hematopoietic diseases
Humans
Leukemia, Myeloid, Acute - classification
Leukemia, Myeloid, Acute - genetics
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical sciences
MicroRNAs - genetics
Middle Aged
miRNA
Mutation
Myeloid leukemia
Pathogenesis
Phenotypes
Sequence Analysis, DNA - methods
Tumor suppressor genes
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Title Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
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