Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia.
Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia.
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DOI：
10.1186/s13059-016-0999-8
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发表时间：
2016-06-29
期刊：
影响因子：
12.3
通讯作者：
Buffa FM
中科院分区：
文献类型：
--
作者：
Haider S;McIntyre A;van Stiphout RG;Winchester LM;Wigfield S;Harris AL;Buffa FM
新陈代谢改变是癌症的标志。然而，基因组变化在代谢基因驱动肿瘤代谢转变中的作用仍有待阐明。在这里，我们研究了十种不同癌症类型的基因组和转录组变化。对6538个肿瘤/正常样本的系统性泛癌症分析涵盖了10种主要癌症类型，确定了44个基因的核心代谢特征，这些基因表现出与mRNA表达增加相关的高频体细胞拷贝数增加/扩增（> 20%的病例）（ρ > 0.3，q < 10−3）。使用这些基因的预后分类器在乳腺癌和肾癌的独立数据集中得到证实。有趣的是，这种特征与缺氧密切相关，在缺氧肿瘤中，10种癌症类型中有9种显示出表达增加，10种癌症类型中有5种显示出这些基因的增加/扩增（P ≤ 0.01）。在乳腺癌和结直肠癌细胞系中的进一步验证强调了角鲨烯环氧酶，一种胆固醇生物合成中的需氧酶，是代谢失调的驱动因素，也是在缺氧条件下维持细胞存活的关键因素。这项研究揭示了泛癌代谢转变的体细胞基因组改变，并表明这些基因的基因组适应作为缺氧肿瘤的生存机制。本文的在线版本（doi：10.1186/s13059-016-0999-8）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s13059-016-0999-8) contains supplementary material, which is available to authorized users.