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.

Differences in cancer gene copy number alterations between Epstein‐Barr virus‐positive and Epstein‐Barr virus‐negative nasopharyngeal carcinoma

“…Although specific viral proteins (ie, EBNA1) have been identified to inhibit p53 function, 44 and thereby reduce genomic repair and ultimately increase CNAs, 45 the results of this study do not completely corroborate EBNA1 playing a primary role in CNA in EBV-infected tumor cells as CNA were more common in EBV-negative NPCs before the Bonferroni correction. However, an argument in favor of CNA playing a tumorigenic role in EBV-positive NPC is the association with worse survival.…”

Cellular Stress Associated with Aneuploidy

“…Other studies demonstrated that unicellular organisms, such as budding yeast or the pathogenic fungus Candida albicans , although maintaining a euploid state under stress-free conditions or for sexual reproduction, use aneuploidy as a readily available source of heritable variation for evolutionary adaptation to stressful environments (Chen et al, 2012; Kaya et al, 2015; Liu et al, 2015; Pavelka et al, 2010; Ryu et al, 2016; Selmecki et al, 2006; Sunshine et al, 2015; Yona et al, 2012). Accumulating evidence also suggests that specific aneuploid chromosome patterns may be selected during the evolution of cancer (Davoli et al, 2013; Graham et al, 2017). …”

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

“…Further, basal-like breast cancers share numerous molecular features including actionable targets with high-grade serous ovarian cancer (The Cancer Genome Atlas Research Network, 2012a). Copy number alteration patterns were found to be common in breast, ovarian, lung, and uterine samples and were predictive of glycolytic phenotypes (Graham et al, 2017). Squamous cell carcinomas from different anatomical sites share frequent alterations in TP53, PIK3CA, CDKN2A, SOX2, and CCND1 compared to other cancer phenotypes (Schwaederle et al, 2015).…”