Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention.

IF 9.9 1区医学 Q1 ONCOLOGY

JNCI Journal of the National Cancer Institute Pub Date : 2025-06-13 DOI:10.1093/jnci/djaf137

James Yarmolinsky, Matthew A Lee, Evelyn Lau, Ferran Moratalla-Navarro, Emma E Vincent, Ruifang Li-Gao, Patrick C N Rensen, Ko Willems van Dijk, Kostas K Tsilidis, Apiwat Sangphukieo, Elmira Ebrahimi, Jochen Hampe, Loïc Le Marchand, Franzel J B van Duijnhoven, Kala Visvanathan, Michael O Woods, Marcela Guevara, Sabina Sieri, Giovanna Masala, Keren Papier, Shama Virani, Tom Dudding, Abbas Dehghan, Alexander G Smith, Dennis Wang, Victor Moreno, Marc J Gunter, Ioanna Tzoulaki

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引用次数: 0

Abstract

Background: The role of lipid-perturbing medications in cancer risk is unclear.

Methods: We employed cis-Mendelian randomization and colocalisation to evaluate the role of 5 lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, PCSK9) in risk of 5 cancers (breast, colorectal, head and neck, ovarian, prostate). We triangulated findings using pre-diagnostic protein measures in prospective analyses in EPIC (977 colorectal cancer cases, 4,080 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 tumour ANGPTL4 expression with cancer-specific mortality in TCGA.

Results: 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%CI:0.66-0.89,P=5.52x10-4,PPcolocalisation=0.83). This association was replicated using pre-diagnostic circulating ANGPTL4 concentrations in EPIC (HRlog10 decrease:0.91,95%CI:0.84-0.98,P=0.01) and the UK Biobank (HRSD decrease:0.93,95%CI:0.86-0.99,P=0.03). 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 (P FDR<0.05), including those involved in cellular proliferation, epithelial-to-mesenchymal transition, and bile acid metabolism. In analysis of 465 colon cancer patients, lower ANGPTL4 tumour expression was associated with reduced colorectal cancer-specific mortality risk (HRlog2 decrease:0.66,95%CI:0.50-0.87,P=2.92x10-3).

Conclusions: 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.

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蛋白质基因组学和观察证据表明，ANGPTL4是预防结直肠癌的潜在治疗靶点。

背景：脂质干扰药物在癌症风险中的作用尚不清楚。方法：采用顺式孟德尔随机和共定位方法，评估5种脂质干扰药物靶点（ANGPTL3、ANGPTL4、APOC3、CETP、PCSK9）在5种癌症（乳腺癌、结直肠癌、头颈癌、卵巢癌、前列腺癌）发病中的作用。我们在EPIC（977例结直肠癌病例，4080名亚队列成员）和UK Biobank（860例结直肠癌病例，50177名对照）的前瞻性分析中使用诊断前蛋白质测量对结果进行三角化。为了深入了解ANGPTL4在癌变中的作用机制，我们在BarcUVa-Seq中检测了ANGPTL4 p.E40K功能缺失变体对正常结肠组织中差异基因表达的影响。最后，我们评估了结肠肿瘤ANGPTL4表达与TCGA癌症特异性死亡率的关系。结果：在78,473例病例和107,143例对照分析中，遗传相关的循环ANGPTL4抑制与结直肠癌风险降低相关（ORSD降低：0.76,95%CI:0.66-0.89，P=5.52x10-4, ppcolocation =0.83）。在EPIC （HRlog10降低：0.91,95%CI:0.84-0.98，P=0.01）和UK Biobank （HRSD降低：0.93,95%CI:0.86-0.99，P=0.03）的诊断前循环ANGPTL4浓度也证实了这种关联。在445个结肠组织样本中差异基因表达的基因集富集分析中，ANGPTL4功能缺失下调了几种与癌症相关的生物学途径（P fdr）。结论：我们的综合蛋白质基因组学和观察分析表明，降低循环ANGPTL4浓度对结直肠癌风险具有潜在的保护作用。这些发现支持进一步评估ANGPTL4作为结直肠癌预防的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JNCI Journal of the National Cancer Institute 医学-肿瘤学

CiteScore

17.00

自引率

2.90%

发文量

203

审稿时长

4-8 weeks

期刊介绍： The Journal of the National Cancer Institute is a reputable publication that undergoes a peer-review process. It is available in both print (ISSN: 0027-8874) and online (ISSN: 1460-2105) formats, with 12 issues released annually. The journal's primary aim is to disseminate innovative and important discoveries in the field of cancer research, with specific emphasis on clinical, epidemiologic, behavioral, and health outcomes studies. Authors are encouraged to submit reviews, minireviews, and commentaries. The journal ensures that submitted manuscripts undergo a rigorous and expedited review to publish scientifically and medically significant findings in a timely manner.