Article

The Pediatric Cancer Genome Project

St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, Memphis, Tennessee, USA.
Nature Genetics (Impact Factor: 29.65). 08/2012; 44(6):619-22. DOI: 10.1038/ng.2287
Source: PubMed
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    • "Pediatric solid tu Q2 mors have diverse molecular and cellular features that reflect their unique cellular origins. With the recent completion of sequence analysis of more than 1000 pediatric solid tumor genomes, we now have a broad understanding of the genomic landscape of childhood cancers that are derived from mesodermal, ectodermal, and endodermal lineages (Downing et al., 2012; Chen et al., in preparation). These data provide the foundation to launch new research efforts to address a central question in cancer biology: Why are cells of some lineages more susceptible to malignant transformation at certain developmental stages than are cells of other lineages? "
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    ABSTRACT: Significant advances have been made over the past 25 years in our understanding of the most common adult solid tumors such as breast, colon, lung and prostate cancer. Much less is known about childhood solid tumors because they are rare and because they originate in developing organs during fetal development, childhood and adolescence. It can be very difficult to study the cellular origins of pediatric solid tumors in developing organs characterized by rapid proliferative expansion, growth factor signaling, developmental angiogenesis, programmed cell death, tissue reorganization and cell migration. Not only has the etiology of pediatric cancer remained elusive because of their developmental origins, but it also makes it more difficult to treat. Molecular targeted therapeutics that alter developmental pathway signaling may have devastating effects on normal organ development. Therefore, basic research focused on the mechanisms of development provides an essential foundation for pediatric solid tumor translational research. In this article, we describe new resources available for the developmental biology and oncology research communities. In a companion paper, we present the detailed characterization of an orthotopic xenograft of a pediatric solid tumor derived from sympathoadrenal lineage during development. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Developmental Biology 04/2015; 87. DOI:10.1016/j.ydbio.2015.02.002 · 3.64 Impact Factor
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    • "As next-generation sequencing studies identify novel genetic lesions in cancer, it becomes evident that mutations affecting key regulators of diverse cellular processes ranging from metabolism to protein stability are somatically selected in cancer cells (Downing et al., 2012; Hodis et al., 2012; Zhang et al., 2012). Presumably , these mutations are selected for because they bestow cells with tumorigenic properties while sparing their essential functions. "
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    ABSTRACT: Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.
    Cell 06/2013; 153(7):1552-66. DOI:10.1016/j.cell.2013.05.041 · 33.12 Impact Factor
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    • "The ICGC has collected omic data on more than 3500 tumors. Among these efforts, St. Jude Children's Research Hospital took an initiative to make cancer genome information freely accessible to the global scientific community at www.ebi.ac.uk/ega/organisa- tions/EGAO00000000046 [2]. This site mainly includes the genome sequences (entire genome sequencing with up to a 30-fold "
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    ABSTRACT: In recent years, cancer genome sequencing and other high-throughput studies of cancer genomes have generated many notable discoveries. In this review, Novel genomic alteration mechanisms, such as chromothripsis (chromosomal crisis) and kataegis (mutation storms), and their implications for cancer are discussed. Genomic alterations spur cancer genome evolution. Thus, the relationship between cancer clonal evolution and cancer stems cells is commented. The key question in cancer biology concerns how these genomic alterations support cancer development and metastasis in the context of biological functioning. Thus far, efforts such as pathway analysis have improved the understanding of the functional contributions of genetic mutations and DNA copy number variations to cancer development, progression and metastasis. However, the known pathways correspond to a small fraction, plausibly 5-10%, of somatic mutations and genes with an altered copy number. To develop a comprehensive understanding of the function of these genomic alterations in cancer, an integrative network framework is proposed and discussed. Finally, the challenges and the directions of studying cancer omic data using an integrative network approach are commented. More information: http://www.cancer-systemsbiology.org/.
    Cancer letters 12/2012; 340(2). DOI:10.1016/j.canlet.2012.11.050 · 5.62 Impact Factor
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