A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom. an0435@bristol.ac.uk. School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom. Centre for Research in Biosciences, The Faculty of Health and Applied Sciences, The University of the West of England, Bristol, United Kingdom. Proteomics Facility, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom. Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. School of Public Health, University of Washington, Seattle, Washington. Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. University of Hawaii Cancer Center, Honolulu, Hawaii. Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah. Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands. Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia. Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany. Division of Research, Kaiser Permanente Northern California, Oakland, California. Department of Internal Medicine, University of Utah, Salt Lake City, Utah. Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France. Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain. Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea. Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea. Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts. Department of Family Medicine, University of Virginia, Charlottesville, Virginia. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia. University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia. Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Clalit National Cancer Control Center, Haifa, Israel. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina. Discipline of Genetics, Memorial University of Newfoundland, St. John's, Canada. Department of General Surgery, University Hospital Rostock, Rostock, Germany. Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden. Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. University of Southern California, Preventative Medicine, Los Angeles, California. Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington. Massachusetts General Hospital and Harvard Medical School, Clinical and Translational Epidemiology Unit, Boston, Massachusetts. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021;(3):564-575

Abstract

BACKGROUND Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.