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

By Aayah Nounu, Alexander Greenhough, Kate 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 JB van Duijnhoven, Andrea Gsur, Peter T. Campbell, Victor 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 J. Gallinger, Heather Hampel, Sonja I. Berndt, Paul Pharoah, Annika Lindblom, Alicja Wolk, Anna H. Wu, Emily White, Ulrike Peters, David A. Drew, Dominique Scherer, Justo Lorenzo Bermejo, Ann C. Williams, Caroline Relton

Posted 14 Aug 2020
bioRxiv DOI: 10.1101/2020.08.14.239871

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 labelling 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). Conclusion: 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. ### Competing Interest Statement The authors have declared no competing interest.

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