Abstract 6429: Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention
Cancer Research, vol. 85, pp. 6429
Abstract
Abstract Background: Preclinical, observational, and genetic epidemiological evidence implicate circulating lipids in cancer development. The role of approved and emerging lipid-perturbing medications in cancer risk is unclear. Patients and Methods: We employed cis-Mendelian randomization (MR) and colocalization 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) in up to 319, 661 cases and 348, 078 controls. We further triangulated findings using direct measures of pre-diagnostic protein targets in case-cohort analyses in the European Prospective Investigation into cancer and Nutrition (EPIC). 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 the BarcUVa-Seq project. Finally, we evaluated the association of ANGPTL4 gene expression in colon tumor tissue with all-cause mortality in The Cancer Genome Atlas (TCGA). Results: In analysis of 78, 473 cases and 107, 143 controls, genetically-proxied circulating ANGPTL4 inhibition was associated with a reduced risk of colorectal cancer (OR per SD decrease: 0.76, 95% CI 0.66-0.89, P = 5.52 x 10-4, colocalization posterior probability = 0.83). This association was replicated in the EPIC cohort using pre-diagnostic circulating ANGPTL4 concentrations in 977 incident colorectal cancer cases and 4, 080 sub-cohort members (HR per log10 decrease: 0.92, 95% CI 0.85-0.99, P = 0.02). In gene set enrichment analysis of differential gene expression in 445 normal colon tissue samples, ANGPTL4 loss-of-function was associated with down-regulation of several biological pathways implicated in cancer (FDR P < 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 expression in tumor tissue was associated with reduced risk of all-cause mortality (HR per log2 decrease: 0.85, 95% CI 0.73-0.99; P = 0.04). There was little evidence of association of genetically-proxied inhibition of ANGPTL4 or other lipid targets with the other cancer outcomes evaluated. Conclusion: Our integrative proteogenomic and observational analyses suggest a protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk. These findings support further evaluation of ANGPTL4, an emerging drug target for hypertriglyceridemia, as a potential therapeutic target for colorectal cancer prevention. Citation Format: James Yarmolinsky, Matthew A. Lee, Evelyn Lau, Ferran Moratalla-Navarro, Emma E. Vincent, Ruifang Li-Gao, Patrick C. Rensen, Ko Willems van Dijk, Kostas K. Tsilidis, Apiwat Sangphukieo, Elmira Ebrahimi, Jochen Hampe, Loic Le Marchand, Franzel J. van Duijnhoven, Kala Visvanathan, Michael O. Woods, Marcela Guevara, Sabina Sieri, Giovanna Masala, Keren Papier, Shama Virani, Tom Dudding, Abbas Dehghan, Dennis Wang, Victor Moreno, Marc J. Gunter, Ioanna Tzoulaki. Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6429.
Authors 26
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Affiliation as printed
1Imperial College London, London, United Kingdom;
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Centre international de recherche sur le cancer
Affiliation as printed
2International Agency for Research on Cancer, Lyon, France;
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Agency for Science, Technology and Research
Affiliation as printed
3Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore;
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Affiliation as printed
4Catalan Institute of Oncology, Barcelona, Spain;
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Affiliation as printed
5University of Bristol, Bristol, United Kingdom;
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Ruifang Li‐Gao Aachen
Leiden University Medical Center
Affiliation as printed
6Leiden University Medical Center, Leiden, Netherlands;
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Patrick C.N. Rensen Aachen
Leiden University Medical Center
Affiliation as printed
6Leiden University Medical Center, Leiden, Netherlands;
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Ko Willems van Dijk Aachen
Leiden University Medical Center
Affiliation as printed
6Leiden University Medical Center, Leiden, Netherlands;
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Centre international de recherche sur le cancer
Affiliation as printed
2International Agency for Research on Cancer, Lyon, France;
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Centre international de recherche sur le cancer
Affiliation as printed
2International Agency for Research on Cancer, Lyon, France;
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Technische Universität Dresden
Affiliation as printed
7Technische Universitat Dresden, Dresden, Germany;
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University of Hawaii Cancer Center
Affiliation as printed
8University of Hawaii Cancer Center, Honolulu, HI;
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Wageningen University & Research
Affiliation as printed
9Wageningen University & Research, Wageningen, Netherlands;
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Affiliation as printed
10Johns Hopkins University, Baltimore, MD;
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Memorial University of Newfoundland
Affiliation as printed
11Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada;
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Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Affiliation as printed
12CIBERESP, Madrid, Spain;
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Fondazione IRCCS Istituto Nazionale dei Tumori
Affiliation as printed
13Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;
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Affiliation as printed
14Clinical Epidemiology Unit, Institute for cancer research, prevention and clinical network (ISPRO), Florence, Italy;
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Affiliation as printed
15University of Oxford, Oxford, United Kingdom
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Centre international de recherche sur le cancer
Affiliation as printed
2International Agency for Research on Cancer, Lyon, France;
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Affiliation as printed
5University of Bristol, Bristol, United Kingdom;
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Affiliation as printed
1Imperial College London, London, United Kingdom;
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Affiliation as printed
1Imperial College London, London, United Kingdom;
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Affiliation as printed
4Catalan Institute of Oncology, Barcelona, Spain;
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Affiliation as printed
1Imperial College London, London, United Kingdom;
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Affiliation as printed
1Imperial College London, London, United Kingdom;
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