Format

Send to

Choose Destination
Mol Syst Biol. 2017 Feb 15;13(2):914. doi: 10.15252/msb.20167159.

Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.

Graham NA1,2,3, Minasyan A1,2, Lomova A1,2, Cass A1,2, Balanis NG1,2, Friedman M1,2, Chan S1,2, Zhao S1,2, Delgado A1,2, Go J1,2, Beck L1,2, Hurtz C4, Ng C4, Qiao R2, Ten Hoeve J1,2, Palaskas N1,2, Wu H2,5,6, Müschen M4,7, Multani AS8, Port E9, Larson SM10, Schultz N11,12, Braas D1,2,13, Christofk HR2,5,13, Mellinghoff IK12,14,15,16, Graeber TG17,2,5,13,18.

Author information

1
Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
2
Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
3
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.
4
Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
5
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
6
School of Life Sciences & Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
7
Department of Haematology, University of Cambridge, Cambridge, UK.
8
Department of Genetics, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA.
9
Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
11
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
12
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
13
UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
14
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
15
Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
16
Department of Neurology, Weill Cornell Medical College, New York, NY, USA.
17
Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA tgraeber@mednet.ucla.edu.
18
California NanoSystems Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

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.

KEYWORDS:

DNA copy number alterations; aneuploidy; genomic instability; glycolysis; metabolism

PMID:
28202506
PMCID:
PMC5327725
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center