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Abstract：
Mitotic catastrophe (MC) is a novel form of cell death that plays an important role in the treatment and drug resistance of colon adenocarcinoma (COAD). However, MC related genes in COAD treatment and prognosis evaluation are rarely studied. In this study, the transcriptome data, somatic mutation and copy number variation data were obtained from The Cancer Genome Atlas (TCGA) database. The mitotic catastrophe related genes (MCRGs) were obtained from GENCARDS website. Differential gene analysis was conducted with LIMMA package. Univariate Cox regression analysis was used to identify prognostic related genes. Mutation analysis was performed and displayed by maftools package. RCircos package was used for localizing the position of genes on chromosomes. \"Glmnet\" R package was applied for constructing a risk model via the LASSO regression method. Consensus clustering analyses was implemented for clustering different subtypes. Functional enrichment analysis through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods, immune infiltration analysis via single sample gene set enrichment analysis (ssGSEA), tumor mutation burden and drug sensitivity analysis by pRRophetic R package were also carried out for risk model or molecular subtype\'s assessment. Additionally, the connections between the expression of hub genes and overall survival (OS) were obtained from online Human Protein Atlas (HPA) website. Real-Time Quantitative Polymerase Chain Reaction (RT‑qPCR) further validated the expression of hub genes. A total of 207 differentially expressed MCRGs were selected in the TCGA cohort, 23 of which were significantly associated with OS in COAD patients. Subsequently, we constructed risk score prognostic models with 5 hub MCRGs, including SYCE2, SERPINE1, TRIP6, LIMK1, and EEPD1. The high-risk patients suffered from poorer prognosis. Furthermore, we developed a nomogram that gathered age, sex, staging, and risk score to accurately forecast the clinical survival outcomes in 1, 3, and 5 years. The results of functional enrichment suggested a significant correlation between MCRGs characteristics and cancer progression, with important implications for the immune microenvironment. Moreover, patients who displayed high TMB and high risk score showed worse prognosis, and risk characteristics were associated with different chemotherapeutic agents. Finally, RT‑qPCR verified the increased expression of the five MCRGs in clinical samples. The five MCRGs in the prognostic signature were associated with prognosis, and could be treated as reliable prognostic biomarkers and therapeutic targets for COAD patients with distinct clinicopathological characteristics, thereby providing a foundation for the precise application of pertinent drugs in COAD patients.
摘要：
有丝分裂突变（MC）是一种新型的细胞死亡形式，在结肠腺癌（COAD）的治疗和耐药性中起着重要作用。然而,MC相干基因在COAD医治和预后评价中的研讨较少。在这项研究中,转录组数据，体细胞突变和拷贝数变异数据来自癌症基因组图谱(TCGA)数据库。有丝分裂突变相关基因（MCRGs）来自GENCARDS网站。用LIMMA包进行差异基因分析。单变量Cox回归分析用于鉴定预后相关基因。通过maftools软件包进行突变分析并显示。RCircos包用于定位基因在染色体上的位置。应用“Glmnet”R包通过LASSO回归方法构建风险模型。对不同亚型进行了聚类的一致性聚类分析。通过基因本体论（GO）和京都基因和基因组百科全书（KEGG）方法进行功能富集分析，通过单样本基因集富集分析（ssGSEA）进行免疫浸润分析，还通过pRropheticR包进行了肿瘤突变负荷和药物敏感性分析，以评估风险模型或分子亚型。此外,hub基因表达与总生存期(OS)之间的联系来自在线人类蛋白质图谱(HPA)网站。实时定量聚合酶链反应(RT‑qPCR)进一步验证了hub基因的表达。在TCGA队列中总共选择了207个差异表达的MCRG，其中23例与COAD患者的OS显著相关。随后，我们用5个中心MCRGs构建了风险评分预后模型，包括SYCE2、SERPINE1、TRIP6、LIMK1和EEPD1。高危患者预后较差。此外，我们开发了一个聚集年龄的列线图，性别,分期,和风险评分来准确预测1年、3年和5年的临床生存结果。功能富集的结果表明，MCRGs特征与癌症进展之间存在显着相关性。对免疫微环境具有重要意义。此外，显示高TMB和高风险评分的患者预后较差，风险特征与不同化疗药物相关。最后,RT-qPCR验证了临床样品中5种MCRGs的表达增加。预后特征中的五个MCRG与预后相关，并且可以作为具有不同临床病理特征的COAD患者的可靠预后生物标志物和治疗靶标，从而为相关药物在COAD患者中的精准应用提供了基础。
