Centre of Postgraduate Medical Education, Department of Biochemistry and Molecular Biology, Warsaw, Poland.
Max-Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
Biochim Biophys Acta Mol Basis Dis. 2017 Mar;1863(3):744-752. doi: 10.1016/j.bbadis.2016.12.011. Epub 2016 Dec 22.
Cellular metabolism of renal cell carcinoma (RCC) tumors is disturbed. The clinical significance of these alterations is weakly understood. We aimed to find if changes in metabolic pathways contribute to survival of RCC patients.
35 RCC tumors and matched controls were used for metabolite profiling using gas chromatography-mass spectrometry and transcriptomic analysis with qPCR-arrays targeting the expression of 93 metabolic genes. The clinical significance of obtained data was validated on independent cohort of 468 RCC patients with median follow-up of 43.22months.
The levels of 31 metabolites were statistically significantly changed in RCC tumors compared with controls. The top altered metabolites included beta-alanine (+4.2-fold), glucose (+3.4-fold), succinate (-11.0-fold), myo-inositol (-4.6-fold), adenine (-4.2-fold), uracil (-3.7-fold), and hypoxanthine (-3.0-fold). These disturbances were associated with altered expression of 53 metabolic genes. ROC curve analysis revealed that the top metabolites discriminating between tumor and control samples included succinate (AUC=0.91), adenine (AUC=0.89), myo-inositol (AUC=0.87), hypoxanthine (AUC=0.85), urea (AUC=0.85), and beta-alanine (AUC=0.85). Poor survival of RCC patients correlated (p<0.0001) with altered expression of genes involved in metabolism of succinate (HR=2.7), purines (HR=2.4), glucose (HR=2.4), beta-alanine (HR=2.5), and myo-inositol (HR=1.9).
We found that changes in metabolism of succinate, beta-alanine, purines, glucose and myo-inositol correlate with poor survival of RCC patients.
肾细胞癌（RCC）肿瘤的细胞代谢紊乱。这些改变的临床意义了解甚少。我们旨在研究代谢途径的改变是否有助于 RCC 患者的生存。
使用气相色谱-质谱联用和 qPCR-array 对 35 个 RCC 肿瘤和匹配的对照组织进行代谢产物谱分析，以检测 93 个代谢基因的表达。在中位随访时间为 43.22 个月的 468 例 RCC 患者的独立队列中验证了获得的数据的临床意义。
与对照相比，31 种代谢物在 RCC 肿瘤中的水平有统计学显著差异。改变最明显的代谢物包括β-丙氨酸（+4.2 倍）、葡萄糖（+3.4 倍）、琥珀酸（-11.0 倍）、肌醇（-4.6 倍）、腺嘌呤（-4.2 倍）、尿嘧啶（-3.7 倍）和次黄嘌呤（-3.0 倍）。这些变化与 53 个代谢基因的表达改变有关。ROC 曲线分析显示，区分肿瘤和对照样本的最佳代谢物包括琥珀酸（AUC=0.91）、腺嘌呤（AUC=0.89）、肌醇（AUC=0.87）、次黄嘌呤（AUC=0.85）、尿素（AUC=0.85）和β-丙氨酸（AUC=0.85）。RCC 患者的不良生存与参与琥珀酸（HR=2.7）、嘌呤（HR=2.4）、葡萄糖（HR=2.4）、β-丙氨酸（HR=2.5）和肌醇（HR=1.9）代谢的基因表达改变相关（p<0.0001）。
我们发现琥珀酸、β-丙氨酸、嘌呤、葡萄糖和肌醇代谢的改变与 RCC 患者的不良生存相关。
