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一种新型脂肪酸代谢相关基因特征可预测结肠腺癌患者的预后、肿瘤免疫特性及免疫治疗反应。

A novel fatty acid metabolism-related gene signature predicts the prognosis, tumor immune properties, and immunotherapy response of colon adenocarcinoma patients.

作者信息

Liu Le, Liang Liping, Mai Genghui, Chen Ye

机构信息

Department of Gastroenterology, Integrated Clinical Microecology Center, Shenzhen Hospital Southern Medical University Shenzhen China.

Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital Southern Medical University Guangzhou China.

出版信息

FASEB Bioadv. 2022 Jun 13;4(9):585-601. doi: 10.1096/fba.2022-00017. eCollection 2022 Sep.

Abstract

Colon adenocarcinoma (COAD) has a high incidence and death rate. Despite the fact that change in fatty acid metabolism promotes tumor growth and metastasis to the greatest degree among metabolite profiles, a thorough investigation on the involvement of fatty acid metabolism-related genes (FAMRGs) in COAD has yet not been conducted. Here, the clinical data as well as the gene expression profiles were extracted from The Cancer Genome Atlas (TCGA) database. Based on the FAMRG expression data and clinical information, a FAMRG risk signature was developed using LASSO as well as multivariate and univariate Cox regression analyses. Then, the nomogram was used to create a customized prognostic prediction model, and the calibration and receiver operating characteristic curves were used to evaluate the nomogram's prediction performance and discriminative capability. Lastly, a number of studies were conducted to assess the influence of independent FAMRGs on COAD, including unsupervised cluster analysis, functional analysis, and drug sensitivity analysis. Three hundred and sixty-seven patients were included in this study, and a 12-FAMRG risk signature was discovered in the training cohort based on a detailed examination of the FAMRGs expression data and clinical information. After that, risk scores were computed to classify patients into low or high-risk groups, and the Kaplan-Meier curve analysis revealed that patients in the low-risk group exhibited an elevated overall survival (OS) rate. The FAMRG was shown to be substantially correlated with prognosis in multivariate Cox regression analysis and was validated using the validation dataset. Then, using the clinical variables and risk signature, we developed and validated a prediction nomogram for OS. Functional characterization showed a strong correlation between this signature and immune cell infiltration and immune modulation. Additionally, by evaluating the GDSC database, it was determined that the high-risk group exhibited medication resistance to many chemotherapeutic and targeted medicines, including VX.680, gemcitabine, doxorubicin, and paclitaxel. Overall, we have revealed the significance of a FAMRG risk signature for predicting the prognosis and response to immunotherapy in COAD, and our findings might contribute to an enhanced comprehension of metabolic pathways and the future development of innovative COAD therapeutic methods.

摘要

结肠癌(COAD)的发病率和死亡率都很高。尽管脂肪酸代谢变化在代谢物谱中对肿瘤生长和转移的促进作用最为显著,但尚未对脂肪酸代谢相关基因(FAMRGs)在COAD中的作用进行全面研究。在此,从癌症基因组图谱(TCGA)数据库中提取了临床数据以及基因表达谱。基于FAMRG表达数据和临床信息,采用LASSO以及多变量和单变量Cox回归分析建立了FAMRG风险特征。然后,使用列线图创建定制的预后预测模型,并使用校准曲线和受试者工作特征曲线来评估列线图的预测性能和判别能力。最后,进行了多项研究以评估独立FAMRGs对COAD的影响,包括无监督聚类分析、功能分析和药物敏感性分析。本研究纳入了367例患者,基于对FAMRGs表达数据和临床信息的详细检查,在训练队列中发现了一个由12个FAMRG组成的风险特征。之后,计算风险评分以将患者分为低风险或高风险组,Kaplan-Meier曲线分析显示低风险组患者的总生存率(OS)有所提高。在多变量Cox回归分析中,FAMRG与预后显著相关,并在验证数据集上得到了验证。然后,利用临床变量和风险特征,我们开发并验证了一个用于OS的预测列线图。功能特征表明该特征与免疫细胞浸润和免疫调节之间存在很强的相关性。此外,通过评估GDSC数据库,确定高风险组对许多化疗药物和靶向药物具有耐药性,包括VX.680、吉西他滨、阿霉素和紫杉醇。总体而言,我们揭示了FAMRG风险特征在预测COAD预后和免疫治疗反应方面的重要性,我们的研究结果可能有助于加深对代谢途径的理解以及未来创新COAD治疗方法的开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f498/9447420/64fefd33b8d8/FBA2-4-585-g008.jpg

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