Yarmolinsky James, Lee Matthew A, Lau Evelyn, Moratalla-Navarro Ferran, Vincent Emma E, Li-Gao Ruifang, Rensen Patrick C N, Willems van Dijk Ko, Tsilidis Kostas K, Sangphukieo Apiwat, Ebrahimi Elmira, Hampe Jochen, Le Marchand Loïc, van Duijnhoven Franzel J B, Visvanathan Kala, Woods Michael O, Guevara Marcela, Sieri Sabina, Masala Giovanna, Papier Keren, Virani Shama, Dudding Tom, Dehghan Abbas, Smith Alexander G, Wang Dennis, Moreno Victor, Gunter Marc J, Tzoulaki Ioanna
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
Nutrition and Metabolism Branch (NME), International Agency for Research on Cancer, Lyon, France.
J Natl Cancer Inst. 2025 Sep 1;117(9):1836-1847. doi: 10.1093/jnci/djaf137.
The role of lipid-perturbing medications in cancer risk is unclear.
We employed cis-Mendelian randomization and colocalization to evaluate the role of 5 lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, and PCSK9) in risk of 5 cancers (breast, colorectal, head and neck, ovarian, and prostate). We triangulated findings using pre-diagnostic protein measures in prospective analyses in EPIC (977 colorectal cancer cases, 4080 sub-cohort members) and the UK Biobank (860 colorectal cancer cases, 50 177 controls). To gain mechanistic insight into the role of ANGPTL4 in carcinogenesis, we examined the impact of the ANGPTL4 p. E40K loss-of-function variant on differential gene expression in normal colon tissue in BarcUVa-Seq. Finally, we evaluated the association of colon tumor ANGPTL4 expression with cancer-specific mortality in TCGA.
In analysis of 78 473 cases and 107 143 controls, genetically proxied circulating ANGPTL4 inhibition was associated with reduced colorectal cancer risk (ORSD decrease = 0.76, 95% confidence interval [CI] = 0.66 to 0.89, P = 5.52 × 10-4, PPcolocalization = 0.83). This association was replicated using pre-diagnostic circulating ANGPTL4 concentrations in EPIC (hazard ratio [HR]log10 decrease = 0.91, 95% CI = 0.84 to 0.98, P = .01) and the UK Biobank (HRSD decrease = 0.93, 95% CI = 0.86 to 0.99, P = .03). In gene-set enrichment analysis of differential gene expression in 445 colon tissue samples, ANGPTL4 loss-of-function down-regulated several cancer-related biological pathways (PFDR < .05), including those involved in cellular proliferation, epithelial-to-mesenchymal transition, and bile acid metabolism. In analysis of 465 colon cancer patients, lower ANGPTL4 tumor expression was associated with reduced colorectal cancer-specific mortality risk (HRlog2 decrease = 0.66, 95% CI = 0.50 to 0.87, P = 2.92 × 10-3).
Our integrative proteogenomic and observational analyses suggest a potential protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk. These findings support further evaluation of ANGPTL4 as a therapeutic target for colorectal cancer prevention.
扰乱脂质的药物在癌症风险中的作用尚不清楚。
我们采用顺式孟德尔随机化和共定位方法，评估5种扰乱脂质的药物靶点（血管生成素样蛋白3、血管生成素样蛋白4、载脂蛋白C3、胆固醇酯转运蛋白和前蛋白转化酶枯草溶菌素9）在5种癌症（乳腺癌、结直肠癌、头颈癌、卵巢癌和前列腺癌）风险中的作用。我们在前瞻性分析中使用EPIC（977例结直肠癌病例，4080名亚队列成员）和英国生物银行（860例结直肠癌病例，50177名对照）中的诊断前蛋白质测量结果对研究结果进行了三角验证。为了深入了解血管生成素样蛋白4在致癌作用中的作用机制，我们在BarcUVa-Seq中研究了血管生成素样蛋白4 p.E40K功能丧失变异对正常结肠组织中差异基因表达的影响。最后，我们在癌症基因组图谱（TCGA）中评估了结肠肿瘤血管生成素样蛋白4表达与癌症特异性死亡率之间的关联。
在对78473例病例和107143名对照的分析中，遗传代理的循环血管生成素样蛋白4抑制与结直肠癌风险降低相关（ORSD降低=0.76，95%置信区间[CI]=0.66至0.89，P=5.52×10-4，PP共定位=0.83）。使用EPIC中诊断前循环血管生成素样蛋白4浓度（对数危险比[HR]降低=0.91，95%CI=0.84至0.98，P=0.01）和英国生物银行（HRSD降低=0.93，95%CI=0.86至0.99，P=0.03）重复了这一关联。在对445个结肠组织样本中差异基因表达的基因集富集分析中，血管生成素样蛋白4功能丧失下调了几种与癌症相关的生物学途径（错误发现率校正P值<0.05），包括那些参与细胞增殖、上皮-间质转化和胆汁酸代谢的途径。在对465例结肠癌患者的分析中，较低的血管生成素样蛋白4肿瘤表达与降低的结直肠癌特异性死亡风险相关（对数2 HR降低=0.66，95%CI=0.50至0.87，P=2.92×10-3）。
我们的综合蛋白质基因组学和观察性分析表明，较低的循环血管生成素样蛋白4浓度在结直肠癌风险中可能具有保护作用。这些发现支持进一步评估血管生成素样蛋白4作为预防结直肠癌的治疗靶点。
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