Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention
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 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) 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 tumour 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 , colocalisation 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 tumour 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. Highlights We used complementary proteogenomic and observational analyses to investigate the effect of lipid-perturbing drug targets on cancer risk Across all methods there was consistent evidence for a protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk Our findings highlight the possibility of repurposing pharmacological ANGPTL4 inhibition as a novel approach for colorectal cancer prevention
Authors 27
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James Yarmolinsky corresponding
Affiliation as printed
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
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Centre international de recherche sur le cancer
Affiliation as printed
Nutrition and Metabolism Branch (NME), International Agency for Research on Cancer, Lyon, France
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Agency for Science, Technology and Research
Affiliation as printed
Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
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Institut d'Investigació Biomédica de Bellvitge · Institut Català d'Oncologia · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Universitat de Barcelona
Affiliation as printed
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
Department of Clinical Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), Faculty of Medicine, University of Barcelona, 08007 Barcelona, Spain
ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
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University of Bristol · MRC Integrative Epidemiology Unit
Affiliation as printed
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK,
Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Patrick C.N. Rensen Aachen Division of Endocrinology Department of Internal Medicine Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Ko Willems van Dijk Aachen Department of Human Genetics Division of Endocrinology Department of Internal Medicine Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
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University of Ioannina · Imperial College London
Affiliation as printed
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
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Centre international de recherche sur le cancer
Affiliation as printed
Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France
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Centre international de recherche sur le cancer
Affiliation as printed
Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France
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Technische Universität Dresden
Affiliation as printed
Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
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University of Hawaii Cancer Center
Affiliation as printed
University of Hawaii Cancer Center, Honolulu, Hawaii, USA
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Wageningen University & Research
Affiliation as printed
Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
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Affiliation as printed
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Memorial University of Newfoundland
Affiliation as printed
Memorial University of Newfoundland, Discipline of Genetics, St. John’s, Canada
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Instituto de Salud Pública de Navarra · Navarre Institute of Health Research · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Affiliation as printed
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
Instituto de Salud Pública y Laboral de Navarra, 31003 Pamplona, Spain
Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
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Fondazione IRCCS Istituto Nazionale dei Tumori
Affiliation as printed
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
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Affiliation as printed
Clinical Epidemiology Unit, Institute for cancer research, prevention and clinical network (ISPRO), Florence, Italy
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Affiliation as printed
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
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Centre international de recherche sur le cancer
Affiliation as printed
Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France
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Affiliation as printed
Bristol Dental School, University of Bristol, Bristol, UK
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Affiliation as printed
Dementia Research Institute, Imperial College London, London United Kingdom
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
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Agency for Science, Technology and Research · Imperial College London
Affiliation as printed
Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
National Heart and Lung Institute, Imperial College London, London, UK
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Institut d'Investigació Biomédica de Bellvitge · Institut Català d'Oncologia · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Universitat de Barcelona
Affiliation as printed
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
Department of Clinical Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), Faculty of Medicine, University of Barcelona, 08007 Barcelona, Spain
ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
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Centre international de recherche sur le cancer · Imperial College London
Affiliation as printed
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Nutrition and Metabolism Branch (NME), International Agency for Research on Cancer, Lyon, France
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Academy of Athens · Biomedical Research Foundation of the Academy of Athens · Imperial College London
Affiliation as printed
Dementia Research Institute, Imperial College London, London United Kingdom
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Systems Biology, Biomedical Research Foundation Academy of Athens, Athens, Greece
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