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      A Children's Oncology Group and TARGET Initiative Exploring the Genetic Landscape of Wilms Tumor

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          Abstract

          Genome-wide sequencing, mRNA and miRNA expression, DNA copy number and methylation analyses were performed on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors ( WT1, CTNNB1, FAM123B, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), mutations were identified in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and let-7a loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

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          Most cited references 51

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          Lin28 Enhances Tumorigenesis and is Associated With Advanced Human Malignancies

          Multiple members of the let-7 family of miRNAs are often repressed in human cancers1,2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3,4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins Lin28 and Lin28B block let-7 precursors from being processed to mature miRNAs5–8, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28/LIN28B with poor clinical prognosis.
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            The Myc/Max/Mad network and the transcriptional control of cell behavior.

            The Myc/Max/Mad network comprises a group of transcription factors whose distinct interactions result in gene-specific transcriptional activation or repression. A great deal of research indicates that the functions of the network play roles in cell proliferation, differentiation, and death. In this review we focus on the Myc and Mad protein families and attempt to relate their biological functions to their transcriptional activities and gene targets. Both Myc and Mad, as well as the more recently described Mnt and Mga proteins, form heterodimers with Max, permitting binding to specific DNA sequences. These DNA-bound heterodimers recruit coactivator or corepressor complexes that generate alterations in chromatin structure, which in turn modulate transcription. Initial identification of target genes suggests that the network regulates genes involved in the cell cycle, growth, life span, and morphology. Because Myc and Mad proteins are expressed in response to diverse signaling pathways, the network can be viewed as a functional module which acts to convert environmental signals into specific gene-regulatory programs.
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              Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

              Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                27 November 2017
                21 August 2017
                October 2017
                21 February 2018
                : 49
                : 10
                : 1487-1494
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, Illinois, 60611, USA
                [2 ]Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA
                [3 ]Division of Hematology-Oncology and Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, 60611, USA
                [4 ]Department of Pathology, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
                [5 ]Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, 20892, USA
                [6 ]Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, 20892, USA
                [7 ]Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, Maryland, 20892, USA
                [8 ]Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency (BCCA), Vancouver, British Columbia, V5Z 4S6, Canada
                [9 ]Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada
                [10 ]Division of Pediatric Hematology/Oncology, Children's National Medical Center, Washington, DC, 20010, USA
                [11 ]Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
                [12 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
                [13 ]Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio, 43205, USA
                [14 ]King Abdullah University of Science and Technology, Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, Thuwal, 23955-6900, Saudi Arabia
                Author notes
                Correspondence: E.J. Perlman, 225 East Chicago Avenue, Box 17, Chicago, Illinois 60611, eperlman@ 123456luriechildrens.org
                Article
                NIHMS896447
                10.1038/ng.3940
                5712232
                28825729

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