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

Nicholas A Graham ,Markus Müschen,Carina Ng,Daniel Braas,Johanna Ten Hoeve,Hong Wu,James Go,Christian Hurtz,Elisa Port,Nikolaus Schultz,Ashley Cass,Nicolaos Palaskas,Michael Friedman,Anastasia Lomova,Aspram Minasyan,Rong Qiao,Shawna T Chan ,Sophie R Zhao ,Ingo K Mellinghoff ,Heather R Christofk ,Asha S Multani ,Adrián Delgado ,Nikolas G Balanis ,L P Beck ,Steven M Larson ,Thomas G Graeber

doi:10.15252/msb.20167159

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.

Highlights

Cancer cells differ from normal cells in that they exhibit aberrant proliferation, resist apoptosis, and invade other tissues (Hanahan & Weinberg, 2011)
To develop an unbiased understanding of DNA copy number alterations (CNAs) in cancer, we performed principal component analysis (PCA) of gene-based Copy number alteration (CNA) data derived from comparative genomic hybridization (CGH) microarrays from 15 tumor types available from The Cancer Genome Atlas (TCGA)
PCA revealed a high degree of similarity in CNA profiles between basal breast invasive carcinoma (BRCA basal), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), and serous uterine corpus endometrial carcinoma (UCEC serous) (Fig 1A and Appendix Fig S1)

Summary

Introduction

Cancer cells differ from normal cells in that they exhibit aberrant proliferation, resist apoptosis, and invade other tissues (Hanahan & Weinberg, 2011). Molecular Systems Biology characterization, including examination of genomic DNA mutations and copy number alterations (CNAs; Stuart & Sellers, 2009). The unexplained recurrent CNA patterns observed in human cancer subtypes are suggestive of additional, not yet fully defined, selective pressures that are conserved across patients and tumor types (Cahill et al, 1999; Sheltzer, 2013; Cai et al, 2016). Reports that the cumulative phenotypic effects of many small gene dosage alterations across the genome can impact the resulting tumor copy number landscape (Solimini et al, 2012; Davoli et al, 2013) illustrate a need to consider more subtle and combinatorial effects to explain the remaining selective forces underlying recurrent CNA patterns observed in human cancers

Methods

Results

Conclusion