Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures
| العنوان: | Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures |
|---|---|
| المؤلفون: | Nikolaus Schultz, Michael C. Friedman, Carina Ng, Johanna ten Hoeve, Nicholas A. Graham, Hong Wu, Nikolas G. Balanis, Anastasia Lomova, Daniel Braas, Sophie Zhao, James Go, Ashley A. Cass, Rong Qiao, Christian Hurtz, Thomas G. Graeber, Adrian Delgado, Shawna Chan, Markus Müschen, Elisa Port, Nicolaos Palaskas, Aspram Minasyan, Steven M. Larson, Lillie Beck, Heather R. Christofk, Ingo K. Mellinghoff, Asha S. Multani |
| المصدر: | Molecular systems biology, vol 13, iss 2 Molecular Systems Biology |
| بيانات النشر: | eScholarship, University of California, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Genome instability, medicine.disease_cause, chemistry.chemical_compound, Neoplasms, Gene duplication, 2.1 Biological and endogenous factors, DNA copy number alterations, Aetiology, Cancer, Genetics, Principal Component Analysis, Tumor, Applied Mathematics, Articles, glycolysis, Phenotype, Gene Expression Regulation, Neoplastic, Computational Theory and Mathematics, Genome-Scale & Integrative Biology, General Agricultural and Biological Sciences, Metabolic Networks and Pathways, Information Systems, Biotechnology, DNA Copy Number Variations, Evolution, Bioinformatics, Enolase, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Genomic Instability, Cell Line, Evolution, Molecular, 03 medical and health sciences, Rare Diseases, Genetic, Cell Line, Tumor, medicine, Humans, aneuploidy, Selection, Genetic, Gene, Selection, Hexokinase, Neoplastic, General Immunology and Microbiology, Gene Expression Profiling, Gene Amplification, Molecular, genomic instability, Gene expression profiling, 030104 developmental biology, chemistry, Gene Expression Regulation, Biochemistry and Cell Biology, Other Biological Sciences, Carcinogenesis, metabolism, Gene Deletion |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f716fc6b11a8964bca84976afd8ddc05 https://escholarship.org/uc/item/6vs2896r |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f716fc6b11a8964bca84976afd8ddc05 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |