Pan Zhen-Kun, Wu Meng-Hua, Shi Hua, Ni Yong-Jian, Geng Quan-Li, Ye Jin-Sheng
Department of General Surgery, Beijing Yanqing Hospital of Traditional Chinese Medicine, Beijing, China.
Department of Urology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
Clin Proteomics. 2025 Jun 4;22(1):24. doi: 10.1186/s12014-025-09545-5.
BACKGROUND: The treatment of advanced or metastatic colorectal cancer (CRC) poses a global challenge. Mendelian Randomization (MR) has been primarily applied for repurposing licensed drugs and uncovering new therapeutic targets. OBJECTIVE: This study aims to systematically identify potential plasma protein targets for CRC using proteome-wide Mendelian randomization and evaluate their potential side effects through phenome-wide association studies (Phe-WAS). METHODS: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of CRC and evaluate their potential side effects through Phe-WAS. The plasma proteins were sourced from the Finland and Iceland decode database, encompassing GWAS data for plasma proteins (Olink-619 samples across 2925 proteins, SomaScan -828 samples across 7596 proteins and Iceland decode database across 4907 proteins). Additionally, GWAS data for CRC were extracted from the UK Biobank-SAIGE database, including 3051 cases and 382,756 controls. Subsequently, colocalization analysis was performed to identify shared causal variants between plasma proteins and CRC. Finally, a phenome-wide association study (Phe-WAS) was conducted to examine the potential adverse effects of druggable proteins for CRC, utilizing the extensive UK Biobank-SAIGE database, encompassing 783 phenotypes. RESULTS: The MR analysis identified GREM1, DKKL1, and CHRDL2 as plasma proteins whose genetically predicted levels were positively associated with CRC risk, whereas TMEM132A was inversely associated with CRC risk (P_fdr < 0.05). The colocalization analysis identified these four proteins as shared variation with CRC (PPH3 + PPH4 > 0.7), suggesting that these proteins represent potential direct targets for CRC intervention. Further phenotype-wide association studies showed no significant potential side effects of these targets (P_fdr > 0.05). CONCLUSION: This proteome-wide Mendelian randomization study offers a comprehensive molecular landscape of CRC, identifying GREM1, DKKL1, CHRDL2, and TMEM132A as potential therapeutic targets. Our research provides a critical foundation for future experimental validation and therapeutic development in colorectal cancer management.
背景：晚期或转移性结直肠癌（CRC）的治疗是一项全球性挑战。孟德尔随机化（MR）主要用于将已获许可的药物重新用于其他用途以及发现新的治疗靶点。 目的：本研究旨在利用全蛋白质组孟德尔随机化系统鉴定结直肠癌潜在的血浆蛋白靶点，并通过全表型关联研究（Phe-WAS）评估其潜在副作用。 方法：我们开展了一项全面的全蛋白质组MR研究，以评估血浆蛋白与结直肠癌风险之间的因果关系，并通过Phe-WAS评估其潜在副作用。血浆蛋白数据来自芬兰和冰岛的解码数据库，包括血浆蛋白的全基因组关联研究（GWAS）数据（Olink - 2925种蛋白质的619个样本，SomaScan - 7596种蛋白质的828个样本以及冰岛解码数据库的4907种蛋白质）。此外，结直肠癌的GWAS数据从英国生物银行 - SAIGE数据库中提取，包括3051例病例和382,756例对照。随后，进行共定位分析以鉴定血浆蛋白与结直肠癌之间共享的因果变异。最后，利用包含783种表型的广泛的英国生物银行 - SAIGE数据库，开展全表型关联研究（Phe-WAS），以检查结直肠癌可成药蛋白的潜在不良反应。 结果：MR分析确定GREM1、DKKL1和CHRDL2为血浆蛋白，其遗传预测水平与结直肠癌风险呈正相关，而TMEM132A与结直肠癌风险呈负相关（P_fdr < 0.05）。共定位分析确定这四种蛋白质与结直肠癌存在共享变异（PPH3 + PPH4 > 0.7），表明这些蛋白质代表结直肠癌干预的潜在直接靶点。进一步的全表型关联研究表明这些靶点无显著潜在副作用（P_fdr > 0.05）。 结论：这项全蛋白质组孟德尔随机化研究提供了结直肠癌全面的分子概况，确定GREM1、DKKL1、CHRDL2和TMEM132A为潜在治疗靶点。我们的研究为未来结直肠癌管理中的实验验证和治疗开发提供了关键基础。
Invest New Drugs. 2024-12
Clin Transl Oncol. 2025-2
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