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https://repository.monashhealth.org/monashhealthjspui/handle/1/26595| Title: | A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer. | Authors: | Pharoah P.D.P.;Nounu A.;Greenhough A.;Heesom K.J.;Richmond R.C.;Zheng J.;Weinstein S.J.;Albanes D.;Gallinger S.;Hampel H.;Berndt S.I.;Lindblom A.;Wolk A.;Wu A.H.;White E.;Peters U.;Drew D.A.;Scherer D.;Bermejo J.L.;Williams A.C.;Relton C.L.;Baron J.A.;Hopper J.L.;Figueiredo J.C.;Newcomb P.A.;Lindor N.M.;Casey G.;Platz E.A.;Le Marchand L.;Ulrich C.M.;Li C.I.;van Duijnhoven F.J.B.;Gsur A.;Campbell P.T.;Moreno V.;Vodicka P.;Vodickova L.;Brenner H.;Chang-Claude J.;Hoffmeister M.;Sakoda L.C.;Slattery M.L.;Schoen R.E.;Gunter M.J.;Castellvi-Bel S.;Kim H.R.;Kweon S.-S.;Chan A.T.;Li L.;Zheng W.;Bishop D.T.;Buchanan D.D.;Giles G.G.;Gruber S.B.;Rennert G.;Stadler Z.K.;Harrison T.A.;Lin Y.;Keku T.O.;Woods M.O.;Schafmayer C.;van Guelpen B. | Institution: | (Nounu, Richmond, Zheng, Relton) Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom (Nounu, Greenhough, Williams) School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom (Greenhough) Centre for Research in Biosciences, Faculty of Health and Applied Sciences, University of the West of England, Bristol, United Kingdom (Heesom) Proteomics Facility, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom (Weinstein, Albanes, Berndt) Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States (Baron) Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States (Hopper) Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia (Hopper) Depart-ment of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea (Figueiredo) Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States (Figueiredo) Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States (Newcomb) Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States (Newcomb) School of Public Health, University of Washington, Seattle, WA, United States (Lindor) Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, United States (Casey) Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States (Platz) Department of Epidemiology, Johns Hopkins Bloom-berg School of Public Health, Baltimore, MD, United States (Le Marchand) University of Hawaii Cancer Center, Honolulu, HI, United States (Ulrich) Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States (Li, Sakoda, Harrison, Lin, White, Peters) Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States (van Duijnhoven) Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands (Gsur) Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria (Campbell) Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, United States (Moreno) Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain (Moreno) CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain (Moreno) Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain (Moreno) ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain (Vodicka, Vodickova) Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia (Vodicka, Vodickova) Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia (Vodicka, Vodickova) Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czechia (Brenner, Hoffmeister) Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany (Brenner) Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany (Brenner) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (Chang-Claude) Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (Chang-Claude) Uni-versity Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany (Sakoda) Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States (Slattery) Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States (Schoen) Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States (Gunter) Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France (Castellvi-Bel) Gastroenterology Department, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain (Kim) Depart-ment of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea (Kweon) Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea (Kweon) Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea (Chan) Divi-sion of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States (Chan) Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States (Chan) Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States (Chan) Broad Institute of Harvard and MIT, Cambridge, MA, United States (Chan) Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States (Chan) Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States (Li) Department of Family Medicine, University of Virginia, Charlottesville, VA, United States (Zheng) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, United States (Bishop) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom (Buchanan) Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Parkville, VIC, Australia (Buchanan) University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia (Buchanan) Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia (Giles) Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia (Giles) Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia (Gruber) Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States (Rennert) Depart-ment of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel (Rennert) Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel (Rennert) Clalit National Cancer Control Center, Haifa, Israel (Stadler) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States (Keku) Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, United States (Woods) Discipline of Genetics, Memorial University of Newfoundland, St. John's, Canada (Schafmayer) Depart-ment of General Surgery, University Hospital Rostock, Rostock, Germany (van Guelpen) Department of Radiation Sciences, Oncology Unit, Umea University, Umea, Sweden (van Guelpen) Wallenberg Centre for Molecular Medicine, Umea University, Umea, Sweden (Gallinger) Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada (Hampel) Division of Human Genetics, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH, United States (Pharoah) Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (Lindblom) Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden (Lindblom) Depart-ment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (Wolk) Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (Wolk) Department of Surgical Sciences, Uppsala University, Uppsala, Sweden (Wu) University of Southern California, Preventative Medicine, Los Angeles, CA, United States (White, Peters) Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, United States (Drew) Massachusetts General Hospital, Harvard Medical School, Clinical and Translational Epidemiology Unit, Boston, MA, United States (Scherer, Bermejo) Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany | Issue Date: | 11-Mar-2021 | Copyright year: | 2021 | Publisher: | American Association for Cancer Research Inc. | Place of publication: | United States | Publication information: | Cancer Epidemiology Biomarkers and Prevention. 30 (3) (pp 564-575), 2021. Date of Publication: March 2021. | Journal: | Cancer Epidemiology Biomarkers and Prevention | 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. Method(s): 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 1/4 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N 1/4 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). Result(s): 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). Conclusion(s): 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.Copyright ©2020 American Association for Cancer Research. | DOI: | http://monash.idm.oclc.org/login?url= http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1158/1055-9965.EPI-20-1176 |
PubMed URL: | 33318029 [http://www.ncbi.nlm.nih.gov/pubmed/?term=33318029] | ISSN: | 1055-9965 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/26595 | Type: | Article | Type of Clinical Study or Trial: | Randomised controlled trial |
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