Clear cell renal cell carcinoma (ccRCC) is the most common and highly malignant pathological type of kidney cancer. We sought to establish a metabolic signature to improve post‐operative risk stratification and identify novel targets in the prediction models for ccRCC patients. A total of 58 metabolic differential expressed genes (MDEGs) were identified with significant prognostic value. LASSO regression analysis constructed 20‐mRNA signatures models, metabolic prediction models (MPMs), in ccRCC patients from two cohorts. Risk score of MPMs significantly predicts prognosis for ccRCC patients in TCGA (P < 0.001, HR = 3.131, AUC = 0.768) and CPTAC cohorts (P = 0.046, HR = 2.893, AUC = 0.777). In addition, G6PC , a hub gene in PPI network of MPMs, shows significantly prognostic value in 718 ccRCC patients from multiply cohorts. Next, G6Pase was detected high expressed in normal kidney tissues than ccRCC tissues. It suggested that low G6Pase expression significantly correlated with poor prognosis (P < 0.0001, HR = 0.316) and aggressive progression (P < 0.0001, HR = 0.414) in 322 ccRCC patients from FUSCC cohort. Meanwhile, promoter methylation level of G6PC was significantly higher in ccRCC samples with aggressive progression status. G6PC significantly participates in abnormal immune infiltration of ccRCC microenvironment, showing significantly negative association with check‐point immune signatures, dendritic cells, Th1 cells, etc. In conclusion, this study first provided the opportunity to comprehensively elucidate the prognostic MDEGs landscape, established novel prognostic model MPMs using large‐scale ccRCC transcriptome data and identified G6PC as potential prognostic target in 1,040 ccRCC patients from multiply cohorts. These finding could assist in managing risk assessment and shed valuable insights into treatment strategies of ccRCC.

中文翻译：

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大规模的转录组概况揭示了健壮的20签名代谢预测模型和G6PC在透明细胞肾细胞癌中的新作用。

透明细胞肾细胞癌（ccRCC）是最常见且高度恶性的肾脏癌病理类型。我们试图建立代谢特征，以改善术后风险分层并在ccRCC患者的预测模型中确定新的靶标。总共鉴定出58个代谢差异表达基因（MDEGs），具有重要的预后价值。LASSO回归分析在来自两个队列的ccRCC患者中构建了20-mRNA特征模型，代谢预测模型（MPM）。MPM的风险评分可显着预测TCGA（P <0.001，HR = 3.131，AUC = 0.768）和CPTAC组（P = 0.046，HR = 2.893，AUC = 0.777 ）的ccRCC患者的预后。另外，G6PCMPM的PPI网络中的中枢基因是718个ccRCC多重队列患者的重要预后价值。接下来，检测到G6Pase在正常肾脏组织中的表达高于ccRCC组织。这表明在FUSCC队列的322例ccRCC患者中，低G6Pase表达与不良预后（P <0.0001，HR = 0.316）和侵袭性进展（P <0.0001，HR = 0.414）显着相关。同时，在具有侵袭性进展状态的ccRCC样品中，G6PC的启动子甲基化水平明显更高。G6PC显着参与ccRCC微环境的异常免疫浸润，与检查点免疫特征，树突状细胞，Th1细胞等呈显着负相关。总之，本研究首先提供了全面阐明MDEG预后的机会，建立了新的预后模型MPM使用大规模ccRCC转录组数据并确定G6PC是来自多个队列的1,040 ccRCC患者的潜在预后目标。这些发现有助于管理风险评估，并为ccRCC的治疗策略提供有价值的见解。