The Pediatric Cancer Genome Project

St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, Memphis, Tennessee, USA.
Nature Genetics (Impact Factor: 29.35). 08/2012; 44(6):619-22. DOI: 10.1038/ng.2287
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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 · 3.55 Impact Factor
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    • "In this study, we characterized the genomic landscape of osteosarcoma by performing whole-genome sequencing (WGS) on 34 osteosarcoma tumor and matched nontumor tissue samples from 32 patients. Our results demonstrate that pediatric osteosarcomas have one of the highest rates of SVs of any pediatric cancer sequenced to date (Downing et al., 2012), but relatively few recurrent single-nucleotide variations (SNVs). However, when SVs and SNVs were combined, inactivating mutations were identified in several cancer pathways. "
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    ABSTRACT: Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs) exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%-53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.
    Cell Reports 04/2014; 7(1). DOI:10.1016/j.celrep.2014.03.003 · 8.36 Impact Factor
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    • "Implementation of such targeted strategies will be more likely successful when used in rationally selected combination regimens, which may allow for lower drug dosing (thereby minimizing overlapping toxicities), decrease acquired drug resistance, and increase potential for additive or synergistic cytotoxicity. At a genomics level, significant collaborative efforts are ongoing via the SJCRH–Washington University Pediatric Cancer Genome Project, the National Cancer Institute’s therapeutically applicable research to generate effective treatments (TARGET) AML Project, and other consortia to delineate more precisely various genetic subgroups of pediatric AML and to identify “actionable” lesions for molecularly targeted therapies (8, 142, 143). "
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    ABSTRACT: Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML in Phase 1 and 2 trials with a smaller number of new agents under Phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remain a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who do not have other curative options.
    Frontiers in Oncology 03/2014; 4:55. DOI:10.3389/fonc.2014.00055
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