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Recurrent Aneuploidy Patterns Enable Fitness Gains in Tumor Metabolism

  • Author(s): Minasyan, Aspram
  • Advisor(s): Graeber, Thomas G
  • et al.
Abstract

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions. These patterns are indicative of conserved selection pressures, but cannot be fully explained by known oncogenes and tumor suppressor genes. Using integrative analysis of CNA data from patient tumors and experimental systems, we report that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including FDG-avidity of patient tumors, and increased proliferation. The primary glycolysis-linked CNA signature is associated with p53 mutation and shows coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes including TIGAR and RPIA. In contrast, alternative signatures involve both different mechanisms of tumor suppression loss (eg, MDM2 amplification) and different glycolysis enzyme isoforms. Furthermore, a cross-species CNA comparison identified 21 conserved CNA regions, containing 13 enzymes in the glycolysis and pentose phosphate pathways in addition to known cancer driving genes. In validation experiments, exogenous expression of hexokinase and enolase enzymes resulted in reduced propensities for amplifications at the corresponding endogenous loci. Our findings support metabolic stress 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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