期刊
MOLECULAR SYSTEMS BIOLOGY
卷 13, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/msb.20167159
关键词
aneuploidy; DNA copy number alterations; genomic instability; glycolysis; metabolism
资金
- National Institutes of Health [P30 CA016042, 5P30 AI028697]
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
- UCLA Chancellor's Office
- UCLA Vice Chancellor's Office of Research
- UCLA Scholars in Oncologic Molecular Imagining Program (NCI/NIH grant) [R25T CA098010]
- UCLA Eugene V. Cota-Robles Fellowship
- UCLA Dissertation Year Fellowship
- NCI/NIH [P50 CA086438, P01 CA168585, P50 CA086306, U19 AI06776]
- American Cancer Society Research Scholar Award [RSG-12-257-01-TBE]
- Melanoma Research Alliance Established Investigator Award [20120279]
- Norton Simon Research Foundation
- UCLA Jonsson Cancer Center Foundation
- National Center for Advancing Translational Sciences UCLA CTSI Grant [UL1TR000124]
- UC Cancer Research Coordinating Committee
- Concern Foundation CONquer CanCER Now Award
- UCLA Stein/Oppenheimer Endowment
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 F-18-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p(53) 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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