title: Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia.
abstract: Altered metabolism is a hallmark of cancer. However, the role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. Here, we have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types.
  
  
  
  A systematic pan-cancer analysis of 6538 tumour/normal samples covering ten major cancer types identified a core metabolic signature of 44 genes that exhibit high frequency somatic copy number gains/amplifications (>20 % cases) associated with increased mRNA expression (ρ > 0.3, q < 10(-3)). Prognostic classifiers using these genes were confirmed in independent datasets for breast and kidney cancers. Interestingly, this signature is strongly associated with hypoxia, with nine out of ten cancer types showing increased expression and five out of ten cancer types showing increased gain/amplification of these genes in hypoxic tumours (P ≤ 0.01). Further validation in breast and colorectal cancer cell lines highlighted squalene epoxidase, an oxygen-requiring enzyme in cholesterol biosynthesis, as a driver of dysregulated metabolism and a key player in maintaining cell survival under hypoxia.
  
  
  
  This study reveals somatic genomic alterations underlying a pan-cancer metabolic shift and suggests genomic adaptation of these genes as a survival mechanism in hypoxic tumours.
authors.affiliation: Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK.|Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.affiliation: Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Ruud G P M
authors.initials: RG
authors.lastname: van Stiphout
authors.affiliation: Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK.|Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Winchester
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Wigfield
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford, UK. Francesca.Buffa@oncology.ox.ac.uk.|Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Francesca.Buffa@oncology.ox.ac.uk.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D014644:Genetic Variation; D042822:Genomic Instability; D023281:Genomics / Q000379:methods; D064593:Heterografts; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D059467:Transcriptome; D000072258:Tumor Hypoxia / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor
keywords: Cancer; Integrative biology; Metabolism; Tumour microenvironment