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 in | The New England journal of medicine Vol. 368; no. 22; pp. 2059 - 2074 | 
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , | 
| Format | Journal Article | 
| Language | English | 
| Published | 
        Waltham, MA
          Massachusetts Medical Society
    
        30.05.2013
     | 
| Subjects | |
| Online Access | Get full text | 
| ISSN | 0028-4793 1533-4406 1533-4406  | 
| DOI | 10.1056/NEJMoa1301689 | 
Cover
| 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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| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27334475$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/23634996$$D View this record in MEDLINE/PubMed  | 
    
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| ContentType | Journal Article | 
    
| Contributor | Wilson, Richard K Kantarjian, Hagop Alonso, Shelley Issa, Jean-Pierre J Backus, Mark Mardis, Elaine R Snyder, Eric E Ayala, Brenda Pot, David A Ozenberger, Bradley A Westervelt, Peter DiPersio, John F Link, Daniel C Carroll, Martin Kahn, Ari Raman, Rohini Jensen, Mark A Wan, Yunhu Bootwalla, Moiz S Lai, Phillip H Wang, Zhining Srinivasan, Deepak Baboud, Julien Chu, Anna L Graubert, Timothy A Berton, Dominique L Walter, Matthew J Pihl, Todd D Sanbhadti, Rashmi N Walton, Jessica Barletta, Sean P Le Beau, Michelle Van Den Berg, David J Shen, Hui Kornblau, Steven Weisenberger, Daniel J Nicholls, Matthew C Girshik, Stanley Kothiyal, Prachi  | 
    
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| Copyright | Copyright © 2013 Massachusetts Medical Society. All rights reserved. 2014 INIST-CNRS Copyright © 2013 Massachusetts Medical Society. 2013  | 
    
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| DOI | 10.1056/NEJMoa1301689 | 
    
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| Issue | 22 | 
    
| Keywords | Human Medicine Acute myelogenous leukemia Genomics Adult Malignant hemopathy Genome De novo Cancer  | 
    
| Language | English | 
    
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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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| 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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