Jiao Jie, Wang Honglei, Sun Danping, Yu Wenbin
Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.
Genet Res (Camb). 2025 May 18;2025:5887056. doi: 10.1155/genr/5887056. eCollection 2025.
The relationship between autoimmune diseases and cancer risk has been increasingly studied. Colorectal cancer, a common malignancy with high morbidity and mortality, has been closely linked to inflammatory bowel disease (IBD) in previous research. However, the association and pathogenesis between primary sclerosing cholangitis (PSC) in autoimmune diseases and colorectal cancer remain incompletely understood. Our study directly investigated the relationship between PSC and colorectal cancer, excluding the influence of IBD, and provided new insights into this association. Mendelian randomization (MR) analysis was first used to investigate the potential causal relationship between PSC and colorectal cancer. Sensitivity analyses were performed to verify the reliability of the MR results. Transcriptomic data were then analyzed based on the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, combined with clinical prognostic data for the final identification of core differential genes. MR analysis demonstrated that genetic susceptibility to PSC was associated with an increased risk of colorectal cancer in a European population cohort (ratio: 1.038, 95% confidence interval: 1.016-1.060, and < 0.001). Furthermore, sensitivity analyses confirmed the robustness of the MR results. Univariate and multivariate Cox analyses identified five core genes: NEDD4L, PPP1R1A, NRG1, KCNJ16, and NECAB2. Patients grouped according to high or low expression of NRG1 showed significant differences in their prognosis ( < 0.001). Our MR study provides evidence that genetic susceptibility to PSC is significantly associated with an increased risk of colorectal cancer in European populations. Analysis of transcriptomic data suggests that NRG1 can be used as a novel biomarker to predict patient prognosis when colorectal cancer and PSC coexist.
自身免疫性疾病与癌症风险之间的关系已得到越来越多的研究。结直肠癌是一种发病率和死亡率都很高的常见恶性肿瘤，先前的研究已将其与炎症性肠病（IBD）紧密联系起来。然而，自身免疫性疾病中的原发性硬化性胆管炎（PSC）与结直肠癌之间的关联及发病机制仍未完全明确。我们的研究直接调查了PSC与结直肠癌之间的关系，排除了IBD的影响，并为这种关联提供了新的见解。首先采用孟德尔随机化（MR）分析来研究PSC与结直肠癌之间的潜在因果关系。进行敏感性分析以验证MR结果的可靠性。然后基于癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）对转录组数据进行分析，并结合临床预后数据以最终鉴定核心差异基因。MR分析表明，在欧洲人群队列中，PSC的遗传易感性与结直肠癌风险增加相关（比值：1.038，95%置信区间：1.016 - 1.060，P < 0.001）。此外，敏感性分析证实了MR结果的稳健性。单因素和多因素Cox分析确定了五个核心基因：NEDD4L、PPP1R1A、NRG1、KCNJ16和NECAB2。根据NRG1高表达或低表达分组的患者在预后方面存在显著差异（P < 0.001）。我们的MR研究提供了证据，表明在欧洲人群中，PSC的遗传易感性与结直肠癌风险增加显著相关。转录组数据分析表明，当结直肠癌与PSC共存时，NRG1可作为预测患者预后的新型生物标志物。
