Journal article
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The New England journal of medicine, Vol.368(22), pp.2059-2074
05/30/2013
DOI: 10.1056/NEJMoa1301689
PMCID: PMC3767041
PMID: 23634996
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.
Details
- Title: Subtitle
- Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
- Creators
- Timothy J. Ley - Washington University in St. LouisChristopher Miller - Washington University in St. LouisLi Ding - Washington University in St. LouisBenjamin J. Raphael - Brown UniversityAndrew J. Mungall - University of British ColumbiaA. Gordon Robertson - British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, CanadaKatherine Hoadley - University of North Carolina at Chapel HillTimothy J. Triche - University of Southern CaliforniaPeter W. Laird - University of Southern CaliforniaJack D. Baty - Washington University in St. LouisLucinda L. Fulton - Washington University in St. LouisRobert Fulton - Washington University in St. LouisSharon E. Heath - Washington University in St. LouisJoelle Kalicki-Veizer - Washington University in St. LouisCyriac Kandoth - Washington University in St. LouisJeffery M. Klco - Washington University in St. LouisDaniel C. Koboldt - Washington University in St. LouisKrishna-Latha Kanchi - Washington University in St. LouisShashikant Kulkarni - Washington University in St. LouisTamara L. Lamprecht - Washington University in St. LouisDavid E. Larson - Washington University in St. LouisLing Lin - Washington Univ, Genome Inst, St Louis, MO 63110 USACharles Lu - Washington University in St. LouisMichael D. McLellan - Washington University in St. LouisJoshua F. McMichael - Washington University in St. LouisJacqueline Payton - Washington University in St. LouisHeather Schmidt - Washington University in St. LouisDavid H. Spencer - Washington Univ, St Louis, MO 63110 USAMichael H. Tomasson - Washington University in St. LouisJohn W. Wallis - Washington University in St. LouisLukas D. Wartman - Washington University in St. LouisMark A. Watson - Washington University in St. LouisJohn Welch - Washington University in St. LouisMichael C. Wendl - Washington University in St. LouisAdrian Ally - University of British ColumbiaMiruna Balasundaram - University of British ColumbiaInanc Birol - University of British ColumbiaYaron Butterfield - British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, CanadaReadman Chiu - University of British ColumbiaAndy Chu - University of British ColumbiaEric Chuah - University of British ColumbiaHye-Jung Chun - University of British ColumbiaRichard Corbett - University of British ColumbiaNoreen Dhalla - University of British ColumbiaRanabir Guin - University of British ColumbiaAn He - University of British ColumbiaCarrie Hirst - University of British ColumbiaMartin Hirst - University of British ColumbiaRobert A. Holt - University of British ColumbiaSteven Jones - British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, CanadaAly Karsan - University of British ColumbiaDarlene Lee - University of British ColumbiaHaiyan I. Li - University of British ColumbiaMarco A. Marra - University of British ColumbiaMichael Mayo - University of British ColumbiaRichard A. Moore - University of British ColumbiaKaren Mungall - British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, CanadaJeremy Parker - University of British ColumbiaErin Pleasance - University of British ColumbiaPatrick Plettner - University of British ColumbiaJacquie Schein - University of British ColumbiaDominik Stoll - University of British ColumbiaLucas Swanson - University of British ColumbiaAngela Tam - University of British ColumbiaNina Thiessen - University of British ColumbiaRichard Varhol - University of British ColumbiaNatasja Wye - University of British ColumbiaYongjun Zhao - University of British ColumbiaStacey Gabriel - Massachusetts Institute of TechnologyGad Getz - Massachusetts Institute of TechnologyCarrie Sougnez - Massachusetts Institute of TechnologyLihua Zou - Massachusetts Institute of TechnologyMark D. M. Leiserson - Brown UniversityFabio Vandin - Brown UniversityHsin-Ta Wu - Brown UniversityFrederick Applebaum - Seattle Cancer Care AllianceStephen B. Baylin - Johns Hopkins UniversityRehan Akbani - The University of Texas MD Anderson Cancer CenterBradley M. Broom - The University of Texas MD Anderson Cancer CenterKen Chen - The University of Texas MD Anderson Cancer CenterThomas C. Motter - The University of Texas MD Anderson Cancer CenterKhanh Nguyen - Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USAJohn N. Weinstein - The University of Texas MD Anderson Cancer CenterNianziang Zhang - The University of Texas MD Anderson Cancer CenterMartin L. Ferguson - MLF Consulting, Boston, MA USAChristopher Adams - Nationwide Children's HospitalAaron Black - Nationwide Children's HospitalJay Bowen - Nationwide Children's HospitalJulie Gastier-Foster - Nationwide Children's HospitalThomas Grossman - Nationwide Children's HospitalTara Lichten-Berg - Nationwide Childrens Hosp, Res Inst, Columbus, OH USALisa Wise - Nationwide Children's HospitalTanja Davidsen - National Institutes of HealthJohn A. Demchok - National Institutes of HealthKenna R. Mills Shaw - National Institutes of HealthMargi Sheth - National Institutes of HealthHeidi J. Sofia - NHGRI, Bethesda, MD 20892 USALiming Yang - National Institutes of HealthJames R. Downing - St Jude Childrens Res Hosp, Memphis, TN 38105 USAGreg EleyShelley Alonso - SRA International (United States)Brenda Ayala - SRA International (United States)Julien Baboud - SRA International (United States)Mark Backus - SRA International (United States)Sean P. Barletta - SRA International (United States)Dominique L. Berton - SRA International (United States)Anna L. Chu - SRA International (United States)Stanley Girshik - SRA International (United States)Mark A. Jensen - SRA International (United States)Ari Kahn - SRA International (United States)Prachi Kothiyal - SRA International (United States)Matthew C. Nicholls - SRA International (United States)Todd D. Pihl - SRA International (United States)David A. Pot - SRA International (United States)Rohini Raman - SRA International (United States)Rashmi N. Sanbhadti - SRA International (United States)Eric E. Snyder - SRA International (United States)Deepak Srinivasan - SRA International (United States)Jessica Walton - SRA Int, Fairfax, VA USAYunhu Wan - SRA International (United States)Zhining Wang - SRA International (United States)Jean-Pierre J. Issa - Temple UniversityMichelle Le Beau - University of ChicagoMartin Carroll - University of PennsylvaniaHagop Kantarjian - Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USASteven Kornblau - Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USAMoiz S. Bootwalla - University of Southern CaliforniaPhillip H. Lai - University of Southern CaliforniaHui Shen - University of Southern CaliforniaDavid J. Van den Berg - University of Southern CaliforniaDaniel J. Weisenberger - University of Southern CaliforniaDaniel C. Link - Washington University in St. LouisMatthew J. Walter - Washington University in St. LouisBradley A. Ozenberger - National Institutes of HealthElaine R. Mardis - Washington University in St. LouisPeter Westervelt - Washington University in St. LouisTimothy A. Graubert - Washington University in St. LouisJohn F. DiPersio - Washington University in St. LouisRichard K. Wilson - Washington University in St. LouisCanc Genome Atlas Res Network
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.368(22), pp.2059-2074
- DOI
- 10.1056/NEJMoa1301689
- PMID
- 23634996
- PMCID
- PMC3767041
- NLM abbreviation
- N Engl J Med
- ISSN
- 0028-4793
- eISSN
- 1533-4406
- Publisher
- Massachusetts Medical Soc
- Number of pages
- 16
- Grant note
- U24CA143845; U24CA143858; U24CA144025; U24CA143882; U24CA143866; U24CA143867; U24CA143848; U24CA143840; U24CA143835; U24CA143799; U24CA143883; U24CA143843; U54HG003067; U54HG003079; U54HG003273; P01CA101937 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U24CA143799 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U54HG003079 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
- Language
- English
- Date published
- 05/30/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984359909202771
Metrics
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