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

Nounu, Aayah; Greenhough, Alexander; Heesom, Kate J.; Richmond, Rebecca C.; Zheng, Jie; Weinstein, Stephanie J.; Albanes, Demetrius; Baron, John A.; Hopper, John L.; Figueiredo, Jane C.; Newcomb, Polly A.; Lindor, Noralane M.; Casey, Graham; Platz, Elizabeth A.; Le Marchand, Loïc; Ulrich, Cornelia M.; Li, Christopher I.; van Duijnhoven, Fränzel J. B.; Gsur, Andrea; Campbell, Peter T.; Moreno, Víctor; Vodicka, Pavel; Vodickova, Ludmila; Brenner, Hermann; Chang-Claude, Jenny; Hoffmeister, Michael; Sakoda, Lori C.; Slattery, Martha L.; Schoen, Robert E.; Gunter, Marc J.; Castellví-Bel, Sergi; Kim, Hyeong Rok; Kweon, Sun-Seog; Chan, Andrew T.; Li, Li; Zheng, Wei; Bishop, D. Timothy; Buchanan, Daniel D.; Giles, Graham G.; Gruber, Stephen B.; Rennert, Gad; Stadler, Zsofia K.; Harrison, Tabitha A.; Lin, Yi; Keku, Temitope O.; Woods, Michael O.; Schafmayer, Clemens; Van Guelpen, Bethany; Gallinger, Steven; Hampel, Heather; Berndt, Sonja I.; Pharoah, Paul D. P.; Lindblom, Annika; Wolk, Alicja;...

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Aayah Nounu

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

Loïc Le Marchand

Cornelia M. Ulrich

Christopher I. Li

Fränzel 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


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


Nounu, A., Greenhough, A., Heesom, K. J., Richmond, R. C., Zheng, J., Weinstein, S. J., …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.

Journal Article Type Article
Acceptance Date Dec 9, 2020
Online Publication Date Dec 14, 2020
Publication Date Mar 1, 2021
Deposit Date Jan 19, 2021
Publicly Available Date Dec 15, 2021
Journal Cancer Epidemiology Biomarkers and Prevention
Print ISSN 1055-9965
Electronic ISSN 1538-7755
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 30
Issue 3
Pages 564-575
Keywords Cancer, Bioinformatics, Epidemiology, Aspirin,
Public URL
Publisher URL
Additional Information Author contributions. A. Greenhough: Conceptualization, data
curation, investigation, methodology, writing-review and editing.


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