背景:结肠癌是胃肠道常见的肿瘤,预后不良。根据研究报告,已经发现泛素依赖性修饰系统在不同类型的恶性肿瘤的发展和进展中起着至关重要的作用。包括结肠癌.然而,需要进一步研究以充分了解结肠癌中泛素化的机制。
方法:我们使用癌症基因组图谱(TCGA)从结肠腺癌(COAD)患者中收集了E3泛素连接酶相关基因(E3RGs)的RNA表达矩阵。“limma”包装用于获得COAD和邻近正常组织之间差异表达的E3RG。然后,进行单变量COX回归和最小绝对收缩和选择算子(LASSO)分析,以构建预后特征和列线图模型。之后,我们使用COAD的原始拷贝数变异数据来发现潜在的体细胞突变,并使用"pRRophetic"软件包来调查高危组和低危组之间化疗药物有效性的差异.还暗示RT-qPCR检测肿瘤组织中的mRNA表达水平。
结果:共筛选了137个差异表达的E3RG3和11个基因(CORO2B,确定了KCTD9,RNF32,BACH2,RBCK1,DPH7,WDR78,UCHL1,TRIM58,WDR72和ZBTB18)用于构建预后特征。Kaplan-Meier曲线显示,在训练和测试队列中,高风险患者的预后较差(P=1.037e-05,P=5.704e-03)。在训练和测试队列中,曲线下面积(AUC)分别为0.728和0.892,分别。基于分层分析,这种11-E3RGs特征是一种新颖且有吸引力的预后模型,独立于几个临床病理参数(年龄,性别,舞台,TNM)在COAD中。对DEG进行GO和KEGG分析,确定了与癌症进展相关的途径。这些途径包括cAMP信号通路,钙信号通路,Wnt信号通路,调节干细胞多能性的信号通路,和蛋白聚糖在癌症中。此外,免疫浸润分析显示巨噬细胞M0、滤泡辅助性T细胞的浸润差异显著,两组之间的浆细胞。
结论:我们开发了一个由11个E3RG组成的新的独立风险模型,并验证了该模型在测试队列中的有效性,提供COAD生存预测的重要见解和COAD治疗的几个有希望的目标。
BACKGROUND: Colon cancer is a common tumor in the gastrointestinal tract with a poor prognosis. According to research reports, ubiquitin-dependent modification systems have been found to play a crucial role in the development and advancement of different types of malignant tumors, including colon cancer. However, further investigation is required to fully understand the mechanism of ubiquitination in colon cancer.
METHODS: We collected the RNA expression matrix of the E3 ubiquitin ligase-related genes (E3RGs) from the patients with colon adenocarcinoma (COAD) using The Cancer Genome Atlas program (TCGA). The \"limma\" package was used to obtain differentially expressed E3RGs between COAD and adjacent normal tissues. Then, univariate COX regression and least absolute shrinkage and selection operator (LASSO) analysis were performed to construct the prognostic signature and nomogram model. Afterward, we used the original copy number variation data of COAD to find potential somatic mutation and employed the \"pRRophetic\" package to investigate the disparity in the effectiveness of chemotherapy drugs between high and low-risk groups. The RT-qPCR was also implied to detect mRNA expression levels in tumor tissues.
RESULTS: A total of 137 differentially expressed E3RG3 were screened and 11 genes (CORO2B, KCTD9, RNF32, BACH2, RBCK1, DPH7, WDR78, UCHL1, TRIM58, WDR72, and ZBTB18) were identified for the construction of prognostic signatures. The Kaplan-Meier curve showed a worse prognosis for patients with high risk both in the training and test cohorts (P = 1.037e-05, P = 5.704e-03), and the area under the curve (AUC) was 0.728 and 0.892 in the training and test cohorts, respectively. Based on the stratified analysis, this 11- E3RGs signature was a novel and attractive prognostic model independent of several clinicopathological parameters (age, sex, stage, TNM) in COAD. The DEGs were subjected to GO and KEGG analysis, which identified pathways associated with cancer progression. These pathways included the cAMP signaling pathway, calcium signaling pathway, Wnt signaling pathway, signaling pathways regulating stem cell pluripotency, and proteoglycans in cancer. Additionally, immune infiltration analysis revealed significant differences in the infiltration of macrophages M0, T cells follicular helper, and plasma cells between the two groups.
CONCLUSIONS: We developed a novel independent risk model consisting of 11 E3RGs and verified the effectiveness of this model in test cohorts, providing important insights into survival prediction in COAD and several promising targets for COAD therapy.