Nath Aritro, Chan Christina
Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.
Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, USA.
Sci Rep. 2016 Jan 4;6:18669. doi: 10.1038/srep18669.
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.
细胞代谢重编程是癌细胞的一个标志性特征。虽然与肿瘤发生相比，有一组独特的过程驱动转移，但尚不清楚代谢途径中的基因改变是否与人类癌症的转移进展相关。在此，我们分析了来自多癌种TCGA数据集的9000多个原发性或转移性肿瘤样本中与糖酵解（瓦伯格效应）、脂肪酸代谢（脂肪生成、氧化、脂肪分解、酯化）和脂肪酸摄取相关的代谢基因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影响所有肿瘤类型预后的瓦伯格效应突变的统一模式，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，我们建立了一个与多种癌症的上皮-间质程序密切相关的基因特征（CAV1、CD36、MLXIPL、CPT1C、CYP2E1）。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，发现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预后不良中的重要作用。
