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

   

Authors:	Graham, N. A.; Minasyan, A.; Lomova, A.; Cass, A.; Balanis, N. G.; Friedman, M.; Chan, S.; Zhao, S.; Delgado, A.; Go, J.; Beck, L.; Hurtz, C.; Ng, C.; Qiao, R.; ten Hoeve, J.; Palaskas, N.; Wu, H.; Müschen, M.; Multani, A. S.; Port, E.; Larson, S. M.; Schultz, N.; Braas, D.; Christofk, H. R.; Mellinghoff, I. K.; Graeber, T. G.
Article 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, 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. © 2017 The Authors. Published under the terms of the CC BY 4.0 license
Keywords:	protein expression; neoplasm; cell proliferation; metabolism; gene amplification; genomic instability; fluorodeoxyglucose f 18; gene dosage; aneuploidy; glycolysis; cell immortalization; hexokinase; synteny; enolase; human; priority journal; article; dna copy number alterations
Journal Title:	Molecular Systems Biology
Volume:	13
Issue:	2
ISSN:	1744-4292
Publisher:	Nature Publishing Group
Date Published:	2017-02-01
Start Page:	914
Language:	English
DOI:	10.15252/msb.20167159
PROVIDER:	scopus
PMCID:	PMC5327725
PUBMED:	28202506
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85013986256&doi=10.15252%2fmsb.20167159&partnerID=40&md5=00b4489908c1b91985595efe79cd6460
Notes:	Article -- Export Date: 3 April 2017 -- Source: Scopus

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