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Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.
Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia; Cass, Ashley; Balanis, Nikolas G; Friedman, Michael; Chan, Shawna; Zhao, Sophie; Delgado, Adrian; Go, James; Beck, Lillie; Hurtz, Christian; Ng, Carina; Qiao, Rong; Ten Hoeve, Johanna; Palaskas, Nicolaos; Wu, Hong; Müschen, Markus; Multani, Asha S; Port, Elisa; Larson, Steven M; Schultz, Nikolaus; Braas, Daniel; Christofk, Heather R; Mellinghoff, Ingo K; Graeber, Thomas G.
Afiliação
  • Graham NA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Minasyan A; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Lomova A; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.
  • Cass A; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Balanis NG; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Friedman M; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Chan S; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Zhao S; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Delgado A; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Go J; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Beck L; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Hurtz C; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Ng C; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Qiao R; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Ten Hoeve J; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Palaskas N; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Wu H; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Müschen M; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Multani AS; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Port E; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Larson SM; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Schultz N; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Braas D; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Christofk HR; Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
  • Mellinghoff IK; Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
  • Graeber TG; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Mol Syst Biol ; 13(2): 914, 2017 02 15.
Article em En | MEDLINE | ID: mdl-28202506
ABSTRACT
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Perfilação da Expressão Gênica / Variações do Número de Cópias de DNA / Glicólise / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
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PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Perfilação da Expressão Gênica / Variações do Número de Cópias de DNA / Glicólise / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article