Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Nature (Impact Factor: 41.46). 12/2008; 456(7218):66-72. DOI: 10.1038/nature07485
Source: PubMed

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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Available from: Michael David Mclellan, Sep 26, 2015
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    • "Recent publications show that the genomes of patients with acute myeloid leukemia (AML) contain hundreds of somatic mutations that accumulate with age (Ley et al. 2008; Mardis et al. 2009; Ding et al. 2012), and that most of these mutations occur as random events in HSCs before one of them acquires a specific pathogenic mutation leading to AML (Welch et al. 2012). Similar patterns of clonal evolution have also been shown for the development of chronic lymphocytic leukemia (CLL) (Landau et al. 2013). "
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    ABSTRACT: The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.
    Genome Research 04/2014; 24(5). DOI:10.1101/gr.162131.113 · 14.63 Impact Factor
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    • "Importantly, the study allowed new molecular probes to be designed to assay events of this type in other patients. Analysis of AML more widely has also shown that heterogeneity in tumors can provide the basis for relapse due to clonal selection of chemotherapy-resistant cell types resulting from new mutations (Ley et al. 2008; Ding et al. 2012). Remissions or poor response to radiation treatment in acute lymphoblastic leukemia (ALL) can also reflect modified double-strand break repair pathways (Marston et al. 2009). "
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    ABSTRACT: The area of plant and animal genomics covers the entire suite of issues in biology because it aims to determine the structure and function of genetic material. Although specific issues define research advances at an organism level, it is evident that many of the fundamental features of genome structure and the translation of encoded information to function share common ground. The Plant and Animal Genome (PAG) conference held in San Diego (California), in January each year provides an overview across all organisms at the genome level, and often it is evident that investments in the human area provide leadership, applications, and discoveries for researchers studying other organisms. This mini-review utilizes the plenary lectures as a basis for summarizing the trends in the genome-level studies of organisms, and the lectures include presentations by Ewan Birney (EBI, UK), Eric Green (NIH, USA), John Butler (NIST, USA), Elaine Mardis (Washington, USA), Caroline Dean (John Innes Centre, UK), Trudy Mackay (NC State University, USA), Sue Wessler (UC Riverside, USA), and Patrick Wincker (Genoscope, France). The work reviewed is based on published papers. Where unpublished information is cited, permission to include the information in this manuscript was obtained from the presenters.
    Functional & Integrative Genomics 03/2014; 14(1). DOI:10.1007/s10142-014-0364-5 · 2.48 Impact Factor
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    • "[16] [17], have provided evidence for the heterogeneity of LSCs attempting to identify the LSC characteristics, for review see [18]. This heterogeneity is further supported by the results of gene sequencing studies, [1] [19] [20]. "
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    ABSTRACT: Recent experimental evidence suggests that acute myeloid leukaemias may originate from multiple clones of malignant cells. Nevertheless, it is not known how the observed clones may differ with respect to cell properties, such as proliferation and self-renewal. There are scarcely any data on how these cell properties change due to chemotherapy and relapse. We propose a new mathematical model to investigate the impact of cell properties on the multi-clonal composition of leukaemias. Model results imply that enhanced self-renewal may be a key mechanism in the clonal selection process. Simulations suggest that fast proliferating and highly self-renewing cells dominate at primary diagnosis, while relapse following therapy-induced remission is triggered mostly by highly self-renewing but slowly proliferating cells. Comparison of simulation results to patient data demonstrates that the proposed model is consistent with clinically observed dynamics based on a clonal selection process.
    Journal of The Royal Society Interface 02/2014; 11(94):20140079. DOI:10.1098/rsif.2014.0079 · 3.92 Impact Factor
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