Choe Eun Kyung, Lee Sangwoo, Kim So Yeon, Shivakumar Manu, Park Kyu Joo, Chai Young Jun, Kim Dokyoon
Department of Surgery, Seoul National University Hospital Healthcare System Gangnam Center, Seoul 06236, Korea.
Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6116, USA.
Cancers (Basel). 2021 Feb 11;13(4):751. doi: 10.3390/cancers13040751.
Background inflammatory status indicators have been reported as prognostic biomarkers of colorectal cancer (CRC). However, since inflammatory interactions with the colon involve various modes of action, the biological mechanism linking inflammation and CRC prognosis has not been fully elucidated. We comprehensively evaluated the predictive roles of the expression and methylation levels of inflammation-related genes for CRC prognosis and their pathophysiological associations.
An integrative analysis of 247 patients with stage I-III CRC from The Cancer Genome Atlas was conducted. Lasso-penalized Cox proportional hazards regression (Lasso-Cox) and statistical Cox proportional hazard regression (CPH) were used for the analysis.
Models to predict overall survival were designed with respective combinations of clinical variables, including age, sex, stage, gene expression, and methylation. An integrative model combining expression, methylation, and clinical features performed better (median C-index = 0.756) than the model with clinical features alone (median C-index = 0.726). Based on multivariate CPH with features from the best model, the methylation levels of CEP250, RAB21, and TNPO3 were significantly associated with overall survival. They did not share any biological process in functional networks. The 5-year survival rate was 29.8% in the low methylation group of CEP250 and 79.1% in the high methylation group ( < 0.001).
Our study results implicate the importance of integrating expression and methylation information along with clinical information in the prediction of survival. CEP250, RAB21, and TNPO3 in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reactions and CRC progression.
背景炎症状态指标已被报道为结直肠癌（CRC）的预后生物标志物。然而，由于炎症与结肠的相互作用涉及多种作用方式，炎症与CRC预后之间的生物学机制尚未完全阐明。我们全面评估了炎症相关基因的表达和甲基化水平对CRC预后的预测作用及其病理生理关联。
对来自癌症基因组图谱的247例I - III期CRC患者进行综合分析。采用套索惩罚的Cox比例风险回归（Lasso - Cox）和统计Cox比例风险回归（CPH）进行分析。
设计了预测总生存期的模型，分别结合了包括年龄、性别、分期、基因表达和甲基化在内的临床变量组合。结合表达、甲基化和临床特征的综合模型（中位C指数 = 0.756）比仅具有临床特征的模型（中位C指数 = 0.726）表现更好。基于具有最佳模型特征的多变量CPH，CEP250、RAB21和TNPO3的甲基化水平与总生存期显著相关。它们在功能网络中没有共享任何生物学过程。CEP250低甲基化组的5年生存率为29.8%，高甲基化组为79.1%（<0.001）。
我们的研究结果表明，在预测生存时整合表达和甲基化信息以及临床信息具有重要意义。预测模型中的CEP250、RAB21和TNPO3可能在CRC预后中起关键作用，并进一步增进我们对炎症反应与CRC进展之间潜在机制的理解。
