Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.
Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.
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DOI：
10.1038/srep18669
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发表时间：
2016-01-04
影响因子：
4.6
通讯作者：
Chan C
中科院分区：
文献类型：
--
作者：
Nath A;Chan C
细胞代谢的重编程是癌细胞的一个标志性特征。虽然与肿瘤发生相比，有一组不同的过程驱动转移，但代谢途径中的基因改变是否与人类癌症的转移进展相关尚不清楚。在此，我们分析了来自多癌症TCGA数据集的9000多个原发性或转移性肿瘤样本中与糖酵解（瓦尔堡效应）、脂肪酸代谢（脂肪生成、氧化、脂解、酯化应是“酯化（酯化作用）”，但此处可能有误，更常见的是“esterification”）和脂肪酸摄取相关的代谢基因的文献衍生模型的突变、拷贝数变异和基因表达模式。我们的关联分析揭示了瓦尔堡效应突变在所有肿瘤类型中影响预后的统一模式，而电子传递链基因SCO2、脂肪酸摄取（CAV1、CD36）和脂肪生成（PPARA、PPARD、MLXIPL）基因的拷贝数改变在转移性肿瘤中富集。利用基因表达谱，我们建立了一个基因特征（CAV1、CD36、MLXIPL、CPT1C、CYP2E1），它与多种癌症中的上皮 - 间质程序密切相关。此外，根据我们分析中确定的基因的拷贝数或表达谱对样本进行分层，显示对患者生存率有显著影响，从而证实了脂肪酸摄取和代谢在人类癌症转移进展和不良预后中的重要作用。
Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers.