title: Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.
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, including18F-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.
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.
authors.forename: Nicholas A
authors.identifier: 0000-0002-6811-1941
authors.initials: NA
authors.lastname: Graham
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Aspram
authors.identifier: 0000-0002-0063-2513
authors.initials: A
authors.lastname: Minasyan
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Anastasia
authors.identifier: 0000-0003-4713-2089
authors.initials: A
authors.lastname: Lomova
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cass
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Nikolas G
authors.initials: NG
authors.lastname: Balanis
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedman
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Shawna
authors.identifier: 0000-0003-0066-079X
authors.initials: S
authors.lastname: Chan
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Delgado
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Go
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Lillie
authors.initials: L
authors.lastname: Beck
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
authors.forename: Christian
authors.identifier: 0000-0001-8346-190X
authors.initials: C
authors.lastname: Hurtz
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
authors.forename: Carina
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Qiao
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ten Hoeve
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Nicolaos
authors.identifier: 0000-0003-0783-0683
authors.initials: N
authors.lastname: Palaskas
authors.affiliation: Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|School of Life Sciences & Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Genetics, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA.
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.affiliation: Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Port
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.affiliation: Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.|Department of Neurology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA tgraeber@mednet.ucla.edu.|Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|California NanoSystems Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Thomas G
authors.identifier: 0000-0001-8574-9181
authors.initials: TG
authors.lastname: Graeber
mesh_terms: D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D019143:Evolution, Molecular; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006019:Glycolysis; D006801:Humans; D053858:Metabolic Networks and Pathways; D009369:Neoplasms / Q000235:genetics*; D025341:Principal Component Analysis; D012641:Selection, Genetic
keywords: DNA copy number alterations; aneuploidy; genomic instability; glycolysis; metabolism