Article
Nature 456, 66-72 (6 November 2008) | doi:10.1038/nature07485; Received 28 May 2008; Accepted 16 September 2008
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome
Timothy J. Ley1,2,3,4,9, Elaine R. Mardis2,3,9, Li Ding2,3, Bob Fulton3, Michael D. McLellan3, Ken Chen3, David Dooling3, Brian H. Dunford-Shore3, Sean McGrath3, Matthew Hickenbotham3, Lisa Cook3, Rachel Abbott3, David E. Larson3, Dan C. Koboldt3, Craig Pohl3, Scott Smith3, Amy Hawkins3, Scott Abbott3, Devin Locke3, LaDeana W. Hillier3,8, Tracie Miner3, Lucinda Fulton3, Vincent Magrini2,3, Todd Wylie3, Jarret Glasscock3, Joshua Conyers3, Nathan Sander3, Xiaoqi Shi3, John R. Osborne3, Patrick Minx3, David Gordon8, Asif Chinwalla3, Yu Zhao1, Rhonda E. Ries1, Jacqueline E. Payton5, Peter Westervelt1,4, Michael H. Tomasson1,4, Mark Watson3,4,5, Jack Baty6, Jennifer Ivanovich4,7, Sharon Heath1,4, William D. Shannon1,4, Rakesh Nagarajan4,5, Matthew J. Walter1,4, Daniel C. Link1,4, Timothy A. Graubert1,4, John F. DiPersio1,4 & Richard K. Wilson2,3,4
- Department of Medicine,
- Department of Genetics,
- The Genome Center at Washington University,
- Siteman Cancer Center,
- Department of Pathology and Immunology,
- Division of Biostatistics, and,
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63108, USA
- Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
- These authors contributed equally to this work.
Correspondence to: Elaine R. Mardis2,3,9 Correspondence and requests for materials should be addressed to E.R.M. (Email: emardis@wustl.edu).
This article is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike licence (http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits distribution, and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation, and derivative works must be licensed under the same or similar licence.
Abstract
Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.
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