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.
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Molecular Oncology Laboratories, Department of Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Cell Line, Tumor, Animals, Humans, Mice, Neoplasms, Cell Transformation, Neoplastic, Disease Models, Animal, Genomic Instability, Prognosis, Cluster Analysis, Gene Expression Profiling, Genomics, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Energy Metabolism, Mutation, Female, Genetic Variation, Genetic Association Studies, DNA Copy Number Variations, Transcriptome, Heterografts, Biomarkers, Tumor, Tumor Hypoxia