Abstract
BackgroundAltered 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.ResultsA 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0999-8) contains supplementary material, which is available to authorized users.
Highlights
Altered metabolism is a hallmark of cancer
Pan-cancer metabolic landscape and increased dysregulation in hypoxic tumours A previously curated list of 2752 metabolic enzyme and transporter genes extracted from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (Additional file 1 and Additional file 2: Table S1) was considered, offering coverage of over-expressed metabolic genes in cancer tissues and association with stemness as well as aggressive breast cancers [13]
Given hypoxia is the main microenvironmental factor associated with dysregulated metabolism [2,3,4,5] and genomic instability [1, 30], we asked whether genomic alterations in metabolic genes are associated with tumour hypoxia
Summary
Altered metabolism is a hallmark of cancer. The role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. We have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types. The role of the microenvironment in driving tumour progression is increasingly recognised. Hypoxia is one of the key physiological and microenvironmental differences between tumour and normal tissues; it induces DNA amplification and damage, whilst reducing repair [1]. It has been recognised that altered gene regulatory networks in cancer drive the activity of metabolic pathways (reviewed in [4]). There is an urgent need for understanding the genetic basis of regulation of metabolic genes, characterising their role in driving tumour growth and assessing their potential as new therapeutic targets
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