Data_Sheet_2_Gene Expression Profiling of Tricarboxylic Acid Cycle and One Carbon Metabolism Related Genes for Prognostic Risk Signature of Colon Carcinoma.xlsx

Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide. Colon adenocarcinoma (COAD) is the most common pathological type of CRC and several biomarkers related to survival have been confirmed. Yet, the predictive effect of a single gene biomarker is not enough. The tricarboxylic acid (TCA) cycle and carbon metabolism play an important role in tumors. Thus, we aimed to identify new gene signatures from the TCA cycle and carbon metabolism to better predict the survival of COAD. This study performed mRNA expression profiling in large COAD cohorts (n = 417) from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression and multivariate Cox regression analysis were performed, and receiver operating characteristic (ROC) curve was used to screen the variable combinations model which is most relevant to patient prognosis survival mostly. Univariable or multivariate analysis results showed that SUCLG2, SUCLG1, ACLY, SUCLG2P2, ATIC and ACO2 have associations with survival in COAD. Combined with clinical variables, we confirmed model 1 (AUC = 0.82505), most relevant to patient prognosis survival. Model 1 contains three genes: SUCLG2P2, SUCLG2 and ATIC, in which SUCLG2P2 and SUCLG2 were low-expressed in COAD, however, ATIC was highly expressed, and the expressions above are related to stages of CRC. Pearson analysis showed that SUCLG2P2, SUCLG2 and ATIC were correlated in normal COAD tissues, while only SUCLG2P2 and SUCLG2 were correlated in tumor tissues. Finally, we verified the expressions of these three genes in COAD samples. Our study revealed a possible connection between the TCA cycle and carbon metabolism and prognosis and showed a TCA cycle and carbon metabolism related gene signature which could better predict survival in COAD patients.

结直肠癌（Colorectal cancer, CRC）是全球范围内最常见的恶性肿瘤之一，其中结肠腺癌（Colon adenocarcinoma, COAD）是CRC最主要的病理亚型，目前已确认多种与患者生存相关的生物标志物，但单一基因标志物的预测效能仍存在局限。三羧酸（Tricarboxylic acid, TCA）循环与碳代谢在肿瘤发生发展过程中发挥关键调控作用，因此本研究旨在从TCA循环及碳代谢相关基因中筛选新型基因特征，以更精准地预测COAD患者的生存预后。
本研究从癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中获取了大型COAD队列（n=417）的mRNA表达谱数据。通过单因素Cox回归、多因素Cox回归分析，并结合受试者工作特征（Receiver Operating Characteristic, ROC）曲线筛选与患者生存预后相关性最高的变量组合模型。
单因素及多因素分析结果显示，SUCLG2、SUCLG1、ACLY、SUCLG2P2、ATIC及ACO2均与COAD患者的生存预后存在显著关联。结合临床变量后，本研究最终确定了与患者生存预后相关性最优的模型1（曲线下面积AUC=0.82505），该模型包含SUCLG2P2、SUCLG2及ATIC三个基因：其中SUCLG2P2与SUCLG2在COAD肿瘤组织中呈低表达状态，而ATIC则呈高表达，且上述基因的表达水平与CRC临床分期显著相关。Pearson相关性分析显示，在正常结肠组织中，SUCLG2P2、SUCLG2与ATIC三者均存在表达相关性；而在COAD肿瘤组织中，仅SUCLG2P2与SUCLG2存在表达相关性。最后，本研究在COAD临床样本中验证了这三个基因的表达水平。
本研究揭示了TCA循环与碳代谢相关调控通路与COAD患者预后的潜在关联，并构建了一个基于TCA循环及碳代谢的基因特征模型，该模型可更有效地预测COAD患者的生存预后。