Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Issue 2 (15th February 2017)

• Record Type: Journal Article
• Authors: Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia; Cass, Ashley; Balanis, Nikolas G; Friedman, Michael; Chan, Shawna; Zhao, Sophie; Delgado, Adrian; Go, James; Beck, Lillie; Hurtz, Christian; Ng, Carina; Qiao, Rong; ten Hoeve, Johanna; Palaskas, Nicolaos; Wu, Hong; Müschen, Markus; Multani, Asha S; Port, Elisa; Larson, Steven M; Schultz, Nikolaus; Braas, Daniel; Christofk, Heather R; Mellinghoff, Ingo K; Graeber, Thomas G
• Is Part Of: Molecular systems biology. Volume 13:Issue 2(2017:Feb.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-02-15
• Subjects: aneuploidy -- DNA copy number alterations -- genomic instability -- glycolysis -- metabolism; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20167159
• Languages: English
• ISSNs: 1744-4292

Abstract

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 18 F‐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. Synopsis: A pan‐cancer and cross‐species analysis of recurrent copy number alteration (CNA) patterns reveals that coordinated CNA of energy metabolism genes provides a selective advantage during tumorigenesis by promoting glycolytic metabolism. Amplifications of glycolysis‐associated genes are conserved and enriched in tumors with high genomic instability, with glycolysis thus functioning as an "oncopathway" in regard to shaping the cancer CNA genome. Copy number signatures predict the glycolytic activity of primary breast cancers and breast cancer cell lines. Genetic manipulation of glycolysis genes prior to the initiation of genomic instability alters the resulting genomic copy number landscape at the endogenous loci. Complex but coordinated DNA copy number changes can contribute to cancer phenotypes in genomically unstable tumors. Abstract : A pan‐cancer and cross‐species analysis of recurrent copy number alteration (CNA) patterns reveals that coordinated CNA of energy metabolism genes provides a selective advantage during tumorigenesis by promoting glycolytic metabolism.