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; Loc Le Marchand; Cornelia M. Ulrich; Christopher I. Li; Franzel J.B. van Duijnhoven; Andrea Gsur; Peter T. Campbell; Víctor Moreno; Pavel Vodicka; Ludmila Vodickova; Hermann Brenner; Jenny Chang-Claude; Michael Hoffmeister; Lori C. Sakoda; Martha L. Slattery; Robert E. Schoen; Marc J. Gunter; Sergi Castellví-Bel; Hyeong Rok Kim; Sun Seog Kweon; Andrew T. Chan; Li Li; Wei Zheng; D. Timothy Bishop; Daniel D. Buchanan; Graham G. Giles; Stephen B. Gruber; Gad Rennert; Zsofia K. Stadler; Tabitha A. Harrison; Yi Lin; Temitope O. Keku; Michael O. Woods; Clemens Schafmayer; Bethany van Guelpen; Steven Gallinger; Heather Hampel; Sonja I. Berndt; Paul D.P. Pharoah; Annika Lindblom; Alicja Wolk; Anna H. Wu; Emily White; Ulrike Peters; David A. Drew; Dominique Scherer; Justo Lorenzo Bermejo; Ann C. Williams; Caroline L. Relton

doi:10.1158/1055-9965.EPI-20-1176

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, Loc Le Marchand, Cornelia M. Ulrich, Christopher I. Li, Franzel J.B. van Duijnhoven, Andrea Gsur, Peter T. CampbellVíctor Moreno, Pavel Vodicka, Ludmila Vodickova, Hermann Brenner, Jenny Chang-Claude, Michael Hoffmeister, Lori C. Sakoda, Martha L. Slattery, Robert E. Schoen, Marc J. Gunter, Sergi Castellví-Bel, Hyeong Rok Kim, Sun Seog Kweon, Andrew T. Chan, Li Li, Wei Zheng, D. Timothy Bishop, Daniel D. Buchanan, Graham G. Giles, Stephen B. Gruber, Gad Rennert, Zsofia K. Stadler, Tabitha A. Harrison, Yi Lin, Temitope O. Keku, Michael O. Woods, Clemens Schafmayer, Bethany van Guelpen, Steven Gallinger, Heather Hampel, Sonja I. Berndt, Paul D.P. Pharoah, Annika Lindblom, Alicja Wolk, Anna H. Wu, Emily White, Ulrike Peters, David A. Drew, Dominique Scherer, Justo Lorenzo Bermejo, Ann C. Williams, Caroline L. Relton

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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 ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 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.

Original language	English (US)
Pages (from-to)	564-575
Number of pages	12
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	30
Issue number	3
DOIs	https://doi.org/10.1158/1055-9965.EPI-20-1176
State	Published - Mar 2021
Externally published	Yes

ASJC Scopus subject areas

Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1055-9965.EPI-20-1176

Cite this

Nounu, A., Greenhough, A., Heesom, K. J., Richmond, R. C., Zheng, J., Weinstein, S. J., Albanes, D., 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., ... Relton, C. L. (2021). A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer. Cancer Epidemiology Biomarkers and Prevention, 30(3), 564-575. https://doi.org/10.1158/1055-9965.EPI-20-1176

Nounu, A, Greenhough, A, Heesom, KJ, Richmond, RC, Zheng, J, Weinstein, SJ, Albanes, D, Baron, JA, Hopper, JL, Figueiredo, JC, Newcomb, PA, Lindor, NM, Casey, G, Platz, EA, Le Marchand, L, Ulrich, CM, Li, CI, van Duijnhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodicka, P, Vodickova, L, Brenner, H, Chang-Claude, J, Hoffmeister, M, Sakoda, LC, Slattery, ML, Schoen, RE, Gunter, MJ, Castellví-Bel, S, Kim, HR, Kweon, SS, Chan, AT, Li, L, Zheng, W, Bishop, DT, Buchanan, DD, Giles, GG, Gruber, SB, Rennert, G, Stadler, ZK, Harrison, TA, Lin, Y, Keku, TO, Woods, MO, Schafmayer, C, van Guelpen, B, Gallinger, S, Hampel, H, Berndt, SI, Pharoah, PDP, Lindblom, A, Wolk, A, Wu, AH, White, E, Peters, U, Drew, DA, Scherer, D, Bermejo, JL, Williams, AC & Relton, CL 2021, 'A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer', Cancer Epidemiology Biomarkers and Prevention, vol. 30, no. 3, pp. 564-575. https://doi.org/10.1158/1055-9965.EPI-20-1176

@article{845aa5fa125f41c5bf55195974df6538,

title = "A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer",

abstract = "Background: Evidence for aspirin{\textquoteright}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 ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 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{\textquoteright}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.",

author = "Aayah Nounu and Alexander Greenhough and Heesom, {Kate J.} and Richmond, {Rebecca C.} and Jie Zheng and Weinstein, {Stephanie J.} and Demetrius Albanes and Baron, {John A.} and Hopper, {John L.} and Figueiredo, {Jane C.} and Newcomb, {Polly A.} and Lindor, {Noralane M.} and Graham Casey and Platz, {Elizabeth A.} and {Le Marchand}, Loc and Ulrich, {Cornelia M.} and Li, {Christopher I.} and {van Duijnhoven}, {Franzel J.B.} and Andrea Gsur and Campbell, {Peter T.} and V{\'i}ctor Moreno and Pavel Vodicka and Ludmila Vodickova and Hermann Brenner and Jenny Chang-Claude and Michael Hoffmeister and Sakoda, {Lori C.} and Slattery, {Martha L.} and Schoen, {Robert E.} and Gunter, {Marc J.} and Sergi Castellv{\'i}-Bel and Kim, {Hyeong Rok} and Kweon, {Sun Seog} and Chan, {Andrew T.} and Li Li and Wei Zheng and Bishop, {D. Timothy} and Buchanan, {Daniel D.} and Giles, {Graham G.} and Gruber, {Stephen B.} and Gad Rennert and Stadler, {Zsofia K.} and Harrison, {Tabitha A.} and Yi Lin and Keku, {Temitope O.} and Woods, {Michael O.} and Clemens Schafmayer and {van Guelpen}, Bethany and Steven Gallinger and Heather Hampel and Berndt, {Sonja I.} and Pharoah, {Paul D.P.} and Annika Lindblom and Alicja Wolk and Wu, {Anna H.} and Emily White and Ulrike Peters and Drew, {David A.} and Dominique Scherer and Bermejo, {Justo Lorenzo} and Williams, {Ann C.} and Relton, {Caroline L.}",

note = "Funding Information: 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{\'e}s Distinguished Professor Award (to A. Wolk). Funding Information: 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). Funding Information: 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). Funding Information: 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. Funding Information: 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{\textquoteright}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. Funding Information: 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 Le{\'o}n (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d{\textquoteright}Oncolog{\'i}a de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: 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). Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-Wu€rttemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: 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. Funding Information: HCES-CRC: the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Funding Information: 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). Funding Information: 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. Funding Information: 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). Funding Information: 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) Funding Information: 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 is a dePass 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). Funding Information: 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). Funding Information: CPS-II: The authors thank the CPS-II participants and Study Management 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. Funding Information: 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. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, 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). Funding Information: 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 Bankhead-Coley 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). Funding Information: 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. Funding Information: CORSA: “Osterreich€ ische Nationalbank Jubil€aumsfondsprojekt” (12511) and Austrian Research Funding Agency (FFG) grant 829675. Funding Information: 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 G{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to M.O. Woods by the Canadian Cancer Society Research Institute. Funding Information: 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 Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G{\'e}n{\'e}tique and the Ligue R{\'e}gionale Contre le Cancer (LRCC). Funding Information: 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 the NCI, 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. Funding Information: 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). Funding Information: 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). Funding Information: 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 G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale, Institut National de la Sant{\'e}et de la Recherche M{\'e}dicale (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 Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska°ne and V€asterbotten (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). Funding Information: NCCCS I & II: The authors acknowledge funding support for this project from the NIH (R01 CA66635 and P30 DK034987). Funding Information: Harvard cohorts (HPFS, NHS, PHS): The study protocol was approved by the institutional review boards of the Brigham and Women{\textquoteright}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 L Giovannucci, 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. Funding Information: The ATBC Study is supported by the Intramural Research Program of the U.S. NCI, NIH. Funding Information: J.A. Baron reports grants from NCI during the conduct of the study; in addition, J.A. Baron, with Dartmouth College, has a patent for Chemopreventive use of aspirin. G. Casey reports grants from NCI during the conduct of the study. E.A. Platz reports personal fees from Kaiser Permanente Northern California, Division of Research outside the submitted work; in addition, E.A. Platz is the editor-in-chief of CEBP. C.M. Ulrich reports grants from NIH during the conduct of the study. V. Moreno reports grants from NIH, Agency for Management of University and Research Grants (AGAUR), and grants from Instituto de Salud Carlos III during the conduct of the study. L.C. Sakoda reports grants from NCI during the conduct of the study. M.L. Slattery reports grants from University of Utah during the conduct of the study. R.E. Schoen reports grants from NIH during the conduct of the study. A.T. Chan reports grants and personal fees from Bayer Pharma AG and Pfizer Inc., and personal fees from Boehringer Ingelheim outside the submitted work. G.G. Giles reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. Z.K. Stadler reports personal fees from Genentech/Roche, Novartis, RegenexBio, Neurogene, Optos Plc, Regeneron, Allergan, Gyroscope Tx, and Adverum outside the submitted work. B. Van Guelpen reports grants from Swedish Research Council, Swedish Cancer Society, Knut and Alice Wallenberg Foundation, Lion{\textquoteright}s Cancer Research Foundation at Umea° University, and Cancer Research Foundation in Northern Sweden during the conduct of the study. H. Hampel reports personal fees and other from Invitae and personal fees from Genome Medical and Promega outside the submitted work. A. Wolk reports grants from The Swedish Research Council and Swedish Cancer Foundation during the conduct of the study. D.A. Drew reports grants from NIH during the conduct of the study. C.L. Relton reports personal fees from Wellcome Trust outside the submitted work. No disclosures were reported by the other authors. Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigaci{\'o}n Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, PI11/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Acci{\'o}n Transversal de C{\'a}ncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Compe-titividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncolog{\'i}a” AEG (Asociaci{\'o}n Espa{\~n}ola de Gastroenterolog{\'i}a), Fundaci{\'o}n Privada Olga Torres, FP7 CHIBCHA Consortium, Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Uni-versitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d{\textquoteright}Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, General-itat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Action BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: 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). Funding Information: 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. Funding Information: NSHDS investigators thank the Biobank Research Unit at Umea° University, the V€asterbotten Intervention Programme, the Northern Sweden MONICA study, and Region V€asterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Funding Information: NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region V€asterbotten; Knut and Alice Wallen-berg Foundation; Lion{\textquoteright}s Cancer Research Foundation at Umea° University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Umea° University, Umea°, Sweden. Publisher Copyright: {\textcopyright}2020 American Association for Cancer Research.",

year = "2021",

month = mar,

doi = "10.1158/1055-9965.EPI-20-1176",

language = "English (US)",

volume = "30",

pages = "564--575",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

TY - JOUR

T1 - A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer

AU - Nounu, Aayah

AU - Greenhough, Alexander

AU - Heesom, Kate J.

AU - Richmond, Rebecca C.

AU - Zheng, Jie

AU - Weinstein, Stephanie J.

AU - Albanes, Demetrius

AU - Baron, John A.

AU - Hopper, John L.

AU - Figueiredo, Jane C.

AU - Newcomb, Polly A.

AU - Lindor, Noralane M.

AU - Casey, Graham

AU - Platz, Elizabeth A.

AU - Le Marchand, Loc

AU - Ulrich, Cornelia M.

AU - Li, Christopher I.

AU - van Duijnhoven, Franzel J.B.

AU - Gsur, Andrea

AU - Campbell, Peter T.

AU - Moreno, Víctor

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - Brenner, Hermann

AU - Chang-Claude, Jenny

AU - Hoffmeister, Michael

AU - Sakoda, Lori C.

AU - Slattery, Martha L.

AU - Schoen, Robert E.

AU - Gunter, Marc J.

AU - Castellví-Bel, Sergi

AU - Kim, Hyeong Rok

AU - Kweon, Sun Seog

AU - Chan, Andrew T.

AU - Li, Li

AU - Zheng, Wei

AU - Bishop, D. Timothy

AU - Buchanan, Daniel D.

AU - Giles, Graham G.

AU - Gruber, Stephen B.

AU - Rennert, Gad

AU - Stadler, Zsofia K.

AU - Harrison, Tabitha A.

AU - Lin, Yi

AU - Keku, Temitope O.

AU - Woods, Michael O.

AU - Schafmayer, Clemens

AU - van Guelpen, Bethany

AU - Gallinger, Steven

AU - Hampel, Heather

AU - Berndt, Sonja I.

AU - Pharoah, Paul D.P.

AU - Lindblom, Annika

AU - Wolk, Alicja

AU - Wu, Anna H.

AU - White, Emily

AU - Peters, Ulrike

AU - Drew, David A.

AU - Scherer, Dominique

AU - Bermejo, Justo Lorenzo

AU - Williams, Ann C.

AU - Relton, Caroline L.

N1 - Funding Information: 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 Institutés Distinguished Professor Award (to A. Wolk). Funding Information: 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). Funding Information: 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). Funding Information: 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. Funding Information: 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. Funding Information: 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 León (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: 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). Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-Wu€rttemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: 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. Funding Information: HCES-CRC: the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Funding Information: 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). Funding Information: 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. Funding Information: 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). Funding Information: 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) Funding Information: 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 is a dePass 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). Funding Information: 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). Funding Information: CPS-II: The authors thank the CPS-II participants and Study Management 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. Funding Information: 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. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, 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). Funding Information: 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 Bankhead-Coley 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). Funding Information: 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. Funding Information: CORSA: “Osterreich€ ische Nationalbank Jubil€aumsfondsprojekt” (12511) and Austrian Research Funding Agency (FFG) grant 829675. Funding Information: 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 Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to M.O. Woods by the Canadian Cancer Society Research Institute. Funding Information: 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 Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). Funding Information: 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 the NCI, 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. Funding Information: 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). Funding Information: 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). Funding Information: 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 Générale de l’Education Nationale, Institut National de la Santéet de la Recherche Médicale (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 Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska°ne and V€asterbotten (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). Funding Information: NCCCS I & II: The authors acknowledge funding support for this project from the NIH (R01 CA66635 and P30 DK034987). Funding Information: 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 L Giovannucci, 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. Funding Information: The ATBC Study is supported by the Intramural Research Program of the U.S. NCI, NIH. Funding Information: J.A. Baron reports grants from NCI during the conduct of the study; in addition, J.A. Baron, with Dartmouth College, has a patent for Chemopreventive use of aspirin. G. Casey reports grants from NCI during the conduct of the study. E.A. Platz reports personal fees from Kaiser Permanente Northern California, Division of Research outside the submitted work; in addition, E.A. Platz is the editor-in-chief of CEBP. C.M. Ulrich reports grants from NIH during the conduct of the study. V. Moreno reports grants from NIH, Agency for Management of University and Research Grants (AGAUR), and grants from Instituto de Salud Carlos III during the conduct of the study. L.C. Sakoda reports grants from NCI during the conduct of the study. M.L. Slattery reports grants from University of Utah during the conduct of the study. R.E. Schoen reports grants from NIH during the conduct of the study. A.T. Chan reports grants and personal fees from Bayer Pharma AG and Pfizer Inc., and personal fees from Boehringer Ingelheim outside the submitted work. G.G. Giles reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. Z.K. Stadler reports personal fees from Genentech/Roche, Novartis, RegenexBio, Neurogene, Optos Plc, Regeneron, Allergan, Gyroscope Tx, and Adverum outside the submitted work. B. Van Guelpen reports grants from Swedish Research Council, Swedish Cancer Society, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation at Umea° University, and Cancer Research Foundation in Northern Sweden during the conduct of the study. H. Hampel reports personal fees and other from Invitae and personal fees from Genome Medical and Promega outside the submitted work. A. Wolk reports grants from The Swedish Research Council and Swedish Cancer Foundation during the conduct of the study. D.A. Drew reports grants from NIH during the conduct of the study. C.L. Relton reports personal fees from Wellcome Trust outside the submitted work. No disclosures were reported by the other authors. Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigación Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, PI11/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Compe-titividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), Fundación Privada Olga Torres, FP7 CHIBCHA Consortium, Agència de Gestió d’Ajuts Uni-versitaris 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, General-itat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Action BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: 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). Funding Information: 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. Funding Information: NSHDS investigators thank the Biobank Research Unit at Umea° University, the V€asterbotten Intervention Programme, the Northern Sweden MONICA study, and Region V€asterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Funding Information: NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region V€asterbotten; Knut and Alice Wallen-berg 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. Publisher Copyright: ©2020 American Association for Cancer Research.

PY - 2021/3

Y1 - 2021/3

N2 - 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 ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 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.

AB - 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 ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 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.

UR - http://www.scopus.com/inward/record.url?scp=85099407187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85099407187&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-20-1176

DO - 10.1158/1055-9965.EPI-20-1176

M3 - Article

C2 - 33318029

AN - SCOPUS:85099407187

SN - 1055-9965

VL - 30

SP - 564

EP - 575

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 3

ER -

A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer

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