460310 Recurrent Patterns of DNA Copy Number Alterations in Tumors Reflect Metabolic Selection Pressures

Thursday, November 17, 2016: 3:33 PM
Continental 8 (Hilton San Francisco Union Square)
Nicholas Graham1,2, Aspram Minasyan2, Anastasia Lomova2, Ashley Cass2, Nikolas Balanis2, Michael Friedman2, Shawna Chan2, Sophie Zhao2, Adrian Delgado2, Lillie Beck2, Christian Hurtz3, Carina Ng3, Rong Qiao2, Johanna ten Hoeve2, Nicolaos Palaskas2, Hong Wu2, Markus Müschen3, Asha Multani4, Elisa Port5, Steven Larson6, Nikolaus Schultz6, Daniel Braas2, Heather Christofk2, Ingo Mellinghoff6 and Thomas Graeber2, (1)Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, (2)Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, (3)University of California, San Francisco, San Francisco, CA, (4)M. D. Anderson Cancer Center, Houston, TX, (5)Mount Sinai Medical Center, New York, NY, (6)Memorial Sloan-Kettering Cancer Center, New York, NY

Human tumors exhibit 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. Applying principal component analysis (PCA) to genome-wide DNA copy number alteration (CNA) from 17 tumor types, we identified previously unreported CNA genomic sub-signatures. Combining these human signatures in a cross-species comparison with signatures from mouse models of cancer allowed for synteny-based elimination of passenger genes. Examination of the cross-species refined CNA signatures revealed coordinate enrichment of copy number alterations in core glycolysis enzymes. Notably, these PCA-defined CNA signatures are predictive of glycolytic phenotypes, including FDG-avidity of patient tumors. Using an experimental immortalization system, we show that exogenous expression of metabolic enzymes alters the copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Finally, using mass spectrometry-based metabolomics, we demonstrate that cells with glycolytic CNA signatures channel an increased proportion of glucose-derived carbon into pentose phosphate-associated biosynthetic pathways including nucleotide synthesis. Taken together, our experimental and computational data support a model in which glycolysis-linked selective pressures encountered during tumorigenesis (eg, redox stress and senescence) shape the highly recurrent DNA copy number alterations found in aneuploid human tumors.

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