Journal article
DNA sequencing of a cytogenetically normal acute myeloid leukemia genome
Nature (London), Vol.456(7218), pp.66-72
11/06/2008
DOI: 10.1038/nature07485
PMCID: PMC2603574
PMID: 18987736
Abstract
Acute myeloid leukemia is a highly malignant hematopoietic tumor that affects about 13,000 adults yearly in the United States. The treatment of this disease has changed little in the past two decades, since most of the genetic events that initiate the disease remain undiscovered. Whole genome sequencing is now possible at a reasonable cost and timeframe to utilize this approach for unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes. Here we show the results obtained by sequencing a typical acute myeloid leukemia genome and its matched normal counterpart, obtained from the patient’s skin. We discovered 10 genes with acquired mutations; two were previously described mutations thought to contribute to tumor progression, and 8 were novel mutations present in virtually all tumor cells at presentation and relapse, whose function is not yet known. Our study establishes whole genome sequencing as an unbiased method for discovering initiating mutations in cancer genomes, and for identifying novel genes that may respond to targeted therapies.
We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical presentation of FAB M1 Acute Myeloid Leukemia (AML) with normal cytogenetics. 32.7-fold ‘haploid’ coverage (98 billion bases) was obtained for the tumor genome, and 13.9-fold coverage (41.8 billion bases) was obtained for the normal sample. Of 2,647,695 well-supported Single Nucleotide Variants (SNVs) found in the tumor genome, 2,588,486 (97.7%) also were detected in the patient’s skin genome, limiting the number of variants that required further study. For the purposes of this initial study, we restricted our downstream analysis to the coding sequences of annotated genes: we found only eight heterozygous, non-synonymous somatic SNVs in the entire genome. All were novel, including mutations in protocadherin/cadherin family members (CDH24 and PCLKC), G-protein coupled receptors (GPR123 and EBI2), a protein phosphatase (PTPRT), a potential guanine nucleotide exchange factor (KNDC1), a peptide/drug transporter (SLC15A1), and a glutamate receptor gene (GRINL1B). We also detected previously described, recurrent somatic insertions in the
FLT3
and
NPM1
genes. Based on deep readcount data, we determined that all of these mutations (except FLT3) were present in nearly all tumor cells at presentation, and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. These results demonstrate the power of whole genome sequencing to discover novel cancer-associated mutations.
Details
- Title: Subtitle
- DNA sequencing of a cytogenetically normal acute myeloid leukemia genome
- Creators
- David Gordon - Department of Genome Sciences, University of Washington, Seattle WAMichael H Tomasson - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOTimothy J Ley - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOElaine R Mardis - Department of Genetics, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOLi Ding - Department of Genetics, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOBob Fulton - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOMichael D McLellan - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOKen Chen - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MODavid Dooling - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOBrian H Dunford-Shore - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOSean McGrath - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOMatthew Hickenbotham - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOLisa Cook - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MORachel Abbott - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MODavid E Larson - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MODan C Koboldt - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOCraig Pohl - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOScott Smith - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOAmy Hawkins - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOScott Abbott - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MODevin Locke - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOLaDeana W Hillier - Department of Genome Sciences, University of Washington, Seattle WATracie Miner - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOLucinda Fulton - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOVincent Magrini - Department of Genetics, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOTodd Wylie - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOJarret Glasscock - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOJoshua Conyers - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MONathan Sander - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOXiaoqi Shi - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOJohn R Osborne - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOPatrick Minx - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOAsif Chinwalla - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOYu Zhao - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MORhonda E Ries - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOJacqueline E Payton - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MOPeter Westervelt - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOMark Watson - The Genome Center at Washington University, Washington University School of Medicine, St. Louis, MOJack Baty - Division of Biostatistics, Washington University School of Medicine, St. Louis, MOJennifer Ivanovich - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MOSharon Heath - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOWilliam D Shannon - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MORakesh Nagarajan - Siteman Cancer Center, Washington University School of Medicine, St. Louis, MOMatthew J Walter - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MODaniel C Link - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOTimothy A Graubert - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MOJohn F DiPersio - Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MORichard K Wilson - Department of Genetics, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MO
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.456(7218), pp.66-72
- DOI
- 10.1038/nature07485
- PMID
- 18987736
- PMCID
- PMC2603574
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 11/06/2008
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094312702771
Metrics
14 Record Views