Chen Quan, Zhou Youtao, Lin Zikai, Yang Cuiyan, Chen Hui, Ke Chuanfeng
Department of Gastrointestinal Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
J Gastrointest Oncol. 2025 Aug 30;16(4):1521-1533. doi: 10.21037/jgo-2025-517. Epub 2025 Aug 27.
Colorectal cancer (CRC) is the third most common cancer worldwide. Despite recent advancements in screening strategies and treatments, the prognosis of CRC patients remains poor. Emerging evidences suggest that tumor immune microenvironment (TIME) and gut microbiota play a pivotal role in CRC progression and treatment. However, the clinical utility of these findings remains limited due to the absence of robust biomarkers. We sought to establish a clinically actionable tool that could guide personalized treatment decisions and ultimately improve outcomes for CRC patients.
We analyzed differentially expressed genes (DEGs) from the Gene Expression Omnibus (GEO) and identified the prognostic genes for CRC by integrating the TIME- and gut microbiota-related genes from GeneCards. Using Mendelian randomization (MR), we examined the causal relationships between the prognostic genes, gut microbiota, and CRC. We then developed a risk model and independently validated its predictive performance using The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COADREAD) dataset as an external validation cohort.
We established a risk model comprising the six identified genes and found that the high-risk group had a significantly higher mortality rate than the low-risk group. Additionally, the high-risk group showed increased immune cell infiltration and a diminished response to immunotherapy. The two-step MR analysis revealed that and mediated the causal relationship between the prognostic genes and CRC. Further, the risk score was shown to be an independent prognostic factor for CRC survival, and the newly established nomogram demonstrated strong concordance between the predicted and observed clinical outcomes.
We developed a six-gene risk model and showed that gut microbes mediate the causal link between the prognostic genes and CRC. Further research on the regulation of the TIME and gut microbiota in CRC may provide valuable insights.
结直肠癌（CRC）是全球第三大常见癌症。尽管近年来筛查策略和治疗方法有所进展，但CRC患者的预后仍然很差。新出现的证据表明，肿瘤免疫微环境（TIME）和肠道微生物群在CRC的进展和治疗中起关键作用。然而，由于缺乏可靠的生物标志物，这些发现的临床应用仍然有限。我们试图建立一种可临床应用的工具，以指导个性化治疗决策并最终改善CRC患者的预后。
我们分析了来自基因表达综合数据库（GEO）的差异表达基因（DEG），并通过整合来自GeneCards的与TIME和肠道微生物群相关的基因，确定了CRC的预后基因。使用孟德尔随机化（MR），我们研究了预后基因、肠道微生物群和CRC之间的因果关系。然后，我们开发了一个风险模型，并使用癌症基因组图谱-结肠腺癌（TCGA-COADREAD）数据集作为外部验证队列，独立验证了其预测性能。
我们建立了一个包含六个已鉴定基因的风险模型，发现高危组的死亡率显著高于低危组。此外，高危组显示免疫细胞浸润增加，对免疫治疗的反应减弱。两步MR分析表明， 和 介导了预后基因与CRC之间的因果关系。此外，风险评分被证明是CRC生存的独立预后因素，新建立的列线图显示预测的和观察到的临床结果之间有很强的一致性。
我们开发了一个六基因风险模型，并表明肠道微生物介导了预后基因与CRC之间的因果联系。对CRC中TIME和肠道微生物群调节的进一步研究可能会提供有价值的见解。
