Journal article

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

Aayah Nounu, Alexander Greenhough, Kate J Heesom, Rebecca C Richmond, Jie Zheng, Stephanie J Weinstein, Demetrius Albanes, John A Baron, John L Hopper, Jane C Figueiredo, Polly A Newcomb, Noralane M Lindor, Graham Casey, Elizabeth A Platz, Loic Le Marchand, Cornelia M Ulrich, Christopher Li, Franzel JB van Duijnhoven, Andrea Gsur, Peter T Campbell Show all

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | AMER ASSOC CANCER RESEARCH | Published : 2021

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 exp..

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Awarded by Cancer Research UK


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Awarded by German Federal Ministry of Education and Research


Awarded by Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): NCI, NIH, U.S. Department of Health and Human Services


Awarded by NIH/NCI Cancer Center


Awarded by ASTERISK: a Hospital Clinical Research Program from the University Hospital Center of Nantes (CHU de Nantes)


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Awarded by COLO23: NIH


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Awarded by ZonMW investment grant


Awarded by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project from the European Union Seventh Framework Programme (FP7/2007-2013)


Awarded by U.S. Department of Health and Human Services


Awarded by National Institutes of Environmental Health Sciences, National Institutes of Health


Awarded by CORSA: "Osterreichische Nationalbank Jubil_aumsfondsprojekt"


Awarded by Austrian Research Funding Agency (FFG)


Awarded by FEDER funds-a way to build Europe


Awarded by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government


Awarded by Junta de Castilla y Leon


Awarded by Xarxa de Bancs de Tumors de Catalunya - Pla Director d'Oncologia de Catalunya (XBTC), Plataforma Biobancos


Awarded by Grant Agency of the Czech Republic (grants CZ GA CR)


Awarded by Grant Agency of the Ministry of Health of the Czech Republic


Awarded by German Research Council


Awarded by NCI, EDRN Grant


Awarded by ERC-2009-AdG (Norway)


Awarded by Health Research Fund (FIS) (Spain)


Awarded by ISCIII RETIC (Spain)


Awarded by Cancer Research UK (United Kingdom)


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Awarded by Fondo de Investigacion Sanitaria/FEDER


Awarded by Xunta de Galicia


Awarded by Ministerio de Economia y Competitividad


Awarded by Fundacion Cientifica de la Asociacion Espanola contra el Cancer


Awarded by Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya)


Awarded by PERIS (Generalitat de Catalunya)


Awarded by COST Action


Awarded by Chonnam National University Hwasun Hospital


Awarded by Australian NHMRC


Awarded by NIH, U.S. Department of Health and Human Services


Awarded by Florida Department of Health BankheadColey Grant


Awarded by Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center


Awarded by Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research


Awarded by National Cancer Institute of Canada


Awarded by NCI of the National NIH


Awarded by Canadian Cancer Society Ontario Research Fund


Awarded by Canadian Institutes of Health Research award


Awarded by NIH, Genes, Environment and Health Initiative (GEI)


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Awarded by National Cancer Institute (NCI) of the National Institutes of Health (NIH)


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Awarded by Swedish Research Council


Awarded by National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services


Awarded by The NIH


Funding Acknowledgements

Author funding: This work was funded by a PhD studentship from the Medical Research Council (to A. Nounu), a Cancer Research UK Programme Grant (C19/A11975; to A.C. Williams), an MRC Research grant (MR/R017247/1; to A.C. Williams), and by the John James Bristol Foundation. Further funding was provided by The UK Medical Research Council Integrative Epidemiology Unit (MC_UU_12013_2; to C.L. Relton) and Cancer Research UK (C18281/A19169; to C.L. Relton), the Wellcome Trust (217487/Z/19/Z; to A. Greenhough), and Bowel CancerUK(19PT0039; to A. Greenhough). R.C. Richmond isa de Pass Vice Chancellor Research Fellow at the University of Bristol. This work was also supported by the German Federal Ministry of Education and Research (01KT1510; to D. Scherer).Consortia funding: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): NCI, NIH, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R21 CA191312, R01201407; to U. Peters). Genotyping/sequencing services were provided by the Center for Inherited Disease Research (CIDR; X01-HG008596 and X-01-HG007585). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704.ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC).The ATBC Study is supported by the Intramural Research Program of the U.S. NCI, NIH.CLUE funding was from the NCI (U01 CA86308, Early Detection Research Network; P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. COLO2&3: NIH (R01 CA60987; to L. Le Marchand).ColoCare: This work was supported by the NIH (R01 CA189184, to C.I. Li and C.M. Ulrich; U01 CA206110, to C.M. Ulrich, C.I. Li, and J.C. Figueiredo; 2P30CA015704-40, R01 CA207371, to C.M. Ulrich and C.I. Li), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative.The Colon Cancer Family Registry (CCFR, www.coloncfr.org) is supported in part by funding from the NCI, NIH (award U01 CA167551). The CCFR Set-1 (Illumina 1M/1M-Duo) and Set-2 (Illumina Omni1-Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143247 (to G. Casey). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to S.B. Gruber). The CCFR Set-4 (Illumina OncoArray 600K SNP array) was supported by NIH award U19 CA148107 (to S.B. Gruber) and by the Center for Inherited Disease Research (CIDR), which is funded by the NIH to the Johns Hopkins University, contract number HHSN268201200008I. The SCCFR Illumina HumanCytoSNP array was supported through NCI award R01 CA076366 (to P.A. Newcomb). Additional funding for the OFCCR/ARCTIC was through award GL201-043 from the Ontario Research Fund, award 112746 from the Canadian Institutes of Health Research, through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society, and through generous support from the Ontario Ministry of Research and Innovation. The content of this manuscript does not necessarily reflect the views or policies of theNCI, NIH, or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR.COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d'Huzes and the Dutch Cancer Society (UM 2012-5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The Nqplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project, which received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public-private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life.Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the NCI/NIH, U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350, to S.B. Gruber; P01 T32 ES013678; R01 CA201407, to U. Peters) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678).CORSA: "Osterreichische Nationalbank Jubil_aumsfondsprojekt" (12511) and Austrian Research Funding Agency (FFG) grant 829675. CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort.CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by Instituto de Salud Carlos III, cofunded by FEDER funds-a way to build Europe(grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y Leon (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncologia de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology.Czech Republic CCS: This work was supported by the Grant Agency of the Czech Republic (grants CZ GA CR: GAP304/10/1286 and 1585) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants AZV 15-27580A and AZV 17-30920A).DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH117/1-1, HO5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B).DALS: NIH (R01 CA48998, to M.L. Slattery).EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06).EPIC: The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRCItaly and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom).EPICOLON: This work was supported by grants from Fondo de Investigacion Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, PI11/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Accion Transversal de Cancer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), Beca Grupo de Trabajo "Oncologia" AEG (Asociacion Espanola de Gastroenterologia), Fundacion Privada Olga Torres, FP7 CHIBCHA Consortium, Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d'Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Action BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III.ESTHER/VERDI. This work was supported by grants from the BadenWurttemberg Ministry of Science, Research and Arts and the German Cancer Aid.Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the NIH (R01 CA137178 and P50 CA127003, to A.T. Chan; P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA151993, R35 CA197735 and K07 CA190673), NHS by the NIH (R01 CA137178 and P50 CA127003, to A.T. Chan; P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673) and PHS by the NIH (R01 CA042182, to J. Ma).Hawaii Adenoma Study: NCI grants R01 CA72520.HCES-CRC: the Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1).Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01 CA136726 (to L. Li).LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167).MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database.Multiethnic Cohort (MEC) Study: NIH (U01 CA164973, to L. Le Marchand; R37 CA54281, P01 CA033619, and R01 CA063464).MECC: This work was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488, to S.B. Gruber and G. Rennert).MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the NIH (grant numbers R01 CA189184, to C.I. Li and C.M. Ulrich; P30 CA076292, to H. Lee Moffitt Cancer Center and Research Institute), Florida Department of Health BankheadColey Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (grant number P30 CA076292 to H. Lee Moffitt Cancer Center and Research Institute). NCCCS I & II: The authors acknowledge funding support for this project from the NIH (R01 CA66635 and P30 DK034987).NCCCS I & II: The authors acknowledge funding support for this project from the NIH (R01 CA66635 and P30 DK034987).NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the NIH, U.S. Department of Health and Human Services (U01 CA74783; to S. Gallinger); and National Cancer Institute of Canada grants (18223 and 18226). The authors acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to M.O. Woods by the Canadian Cancer Society Research Institute.NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region Vasterbotten; Knut and Alice Wallenberg Foundation; Lion's Cancer Research Foundation at Umea University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Umea University, Umea, Sweden.OFCCR: The Ontario Familial Colorectal Cancer Registry was supported in part by the NCI of the National NIH under award U01 CA167551 and award U01/U24 CA074783 (to S. Gallinger). Additional funding for the OFCCR and ARCTIC testing and genetic analysis was through a Canadian Cancer Society CaRE (Cancer Risk Evaluation) program grant and Ontario Research Fund award GL201-043, through the Canadian Institutes of Health Research award 112746, and through generous support from the Ontario Ministry of Research and Innovation. OSUMC: OCCPI funding was provided by Pelotonia and HNPCC funding was provided by the NCI (CA16058 and CA67941).PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, NCI, NIH, DHHS. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438.SCCFR: The Seattle Colon Cancer Family Registry was supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under awards U01 P30 CA015704, U01 CA074794, and U24 CA074794 (to P.A. Newcomb) and R01 CA076366 (to P.A. Newcomb).SEARCH: The University of Cambridge has received salary support in respect of PDPP from the NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge.SELECT: Research reported in this publication was supported in part by the NCI of the NIH under Award Numbers U10 CA37429 and UM1 CA182883. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.SMS: This work was supported by the NCI (grant P01 CA074184, to P.A. Newcomb; grants R01 CA097325, R03 CA153323, and K05 CA152715, to P.A. Newcomb; and the National Center for Advancing Translational Sciences at the NIH (grant KL2 TR000421).The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish Research Council; K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2 and the Stockholm County Council (ALF project).Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institut~es Distinguished Professor Award (to A. Wolk).UK Biobank: This research has been conducted using the UK Biobank Resource under Application Number 8614.VITAL: NIH (K05 CA154337, to E. White).WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.ASTERISK: The authors are very grateful to Dr. Bruno Buecher, without whom this project would not have existed. They also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians, and students.CCFR: The authors are grateful to Mark A. Jenkins, who helped obtain the NCI grant U01 CA167551.CLUE: The authors appreciate the continued efforts of the staff members at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE II study. They thank the participants in CLUE. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control (Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/cancer, 410-767-4055). They acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data.CPS-II: The authors thank the CPS-II participants and StudyManagement Group for their invaluable contributions to this research. The authors also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program.Harvard cohorts (HPFS, NHS, PHS): The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors thank the participants and staff of the HPFS, NHS, and PHS for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. The authors are grateful to Edward LGiovannucci, Walter C. Willett, Shuji Ogino, Reiko Nishihara, and Meir J. Stampfer, who helped secure NIH grant P01 CA055075, U01 CA167552, R35 CA197735, K07 CA190673, and UM1 CA186107, respectively. Edward L. Giovannucci and Shuji Ogino also secured NIH grants P01 CA087969 and R01 CA151993, respectively.NSHDS investigators thank the Biobank Research Unit at Umea University, the Vasterbotten Intervention Programme, the Northern Sweden MONICA study, and Region Vasterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650).