良性及肿瘤实质代谢组学特征影响肾细胞癌手术患者的代偿性肾生长。
Benign and tumor parenchyma metabolomic profiles affect compensatory renal growth in renal cell carcinoma surgical patients.
作者信息
Rosenzweig Barak, Rubinstein Nimrod D, Reznik Ed, Shingarev Roman, Juluru Krishna, Akin Oguz, Hsieh James J, Jaimes Edgar A, Russo Paul, Susztak Katalin, Coleman Jonathan A, Hakimi A Ari
机构信息
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, United States of America.
出版信息
PLoS One. 2017 Jul 20;12(7):e0180350. doi: 10.1371/journal.pone.0180350. eCollection 2017.
BACKGROUND AND OBJECTIVES
Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship.
DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi-lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model, we identified metabolites whose abundances significantly associate with CRG.
RESULTS
Our analysis found 13 metabolites in the benign (e.g. L-urobilin, Variable Influence in Projection, VIP, score = 3.02, adjusted p = 0.017) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate, VIP score = 1.3, adjusted p = 0.044) tissues that significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with that significantly positively associate with CRG (e.g. p-cresol sulfate, VIP score = 2.945, adjusted p = 0.033). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, both pre-operatively and long term, whereas in the tumor tissue significant enrichment of dipeptides and benzoate (positive association), glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways, were observed.
CONCLUSION
These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth.
背景与目的
术前肾体积是肾细胞癌患者肾小球滤过率的独立预测指标。在肾切除术之前，代偿性肾生长（CRG）可与肿瘤生长和良性实质损失同时发生。我们旨在测试肾代谢物丰度是否与CRG显著相关，并提示因果关系。
设计、设置、参与者及测量方法：先前已收集了49例患者的组织代谢组学数据，这些患者的中位年龄为60岁，术前患侧与对侧良性肾体积的变化倍数用作CRG的替代指标。在3.3±2.1年的随访期内对侧肾体积变化倍数用作长期CRG的替代指标。使用多变量统计模型，我们确定了其丰度与CRG显著相关的代谢物。
结果
我们的分析发现，良性组织中有13种代谢物（例如L-尿胆素，投影变量影响，VIP，得分=3.02，校正p=0.017），恶性组织中有163种代谢物（例如3-吲哚硫酸盐，VIP得分=1.3，校正p=0.044）与CRG显著相关。代谢物丰度的良性/肿瘤变化倍数揭示了另外三种与CRG显著正相关的代谢物（例如对甲酚硫酸盐，VIP得分=2.945，校正p=0.033）。在通路水平上，我们表明脂肪酸氧化高度富集了其良性组织丰度在术前和长期均与CRG呈强正相关的代谢物，而在肿瘤组织中，观察到二肽和苯甲酸盐（正相关）、糖酵解/糖异生、溶血磷脂和核苷酸糖戊糖（负相关）子通路的显著富集。
结论
这些数据表明，良性以及肿瘤实质中的特定生物学过程强烈影响代偿性肾生长。
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