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 Melbourne; Jane C Figueiredo; Polly A Newcomb; Noralane M Lindor; Graham Casey; Elizabeth A Platz; Loic Le Marchand; Cornelia M Ulrich; Christopher I Li; Fränzel J B van Duijnhoven; Andrea Gsur; Peter 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; David T 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 L 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 Melbourne, Jane C Figueiredo, Polly A Newcomb, Noralane M Lindor, Graham Casey, Elizabeth A Platz, Loic Le Marchand, Cornelia M Ulrich, Christopher I Li, Fränzel J B van Duijnhoven, Andrea Gsur, Peter CampbellVictor 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, David T 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 L Bermejo, Ann C Williams, Caroline L Relton

^*Corresponding author for this work

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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 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).

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
Journal	Cancer Epidemiology, Biomarkers and Prevention
Early online date	14 Dec 2020
DOIs	https://doi.org/10.1158/1055-9965.EPI-20-1176
Publication status	E-pub ahead of print - 14 Dec 2020

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10.1158/1055-9965.EPI-20-1176

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Investigating the function of the BCL-3/Beta-canetin complex in promoting intestinal tumorigenesis and acquisition of therapeutic resistance
Williams, A. C. (Principal Investigator)
1/07/18 → 30/09/21
Project: Research

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Nounu, A., Greenhough, A., Heesom, K. J., Richmond, R. C., Zheng, J., Weinstein, S. J., Albanes, D., Baron, J. A., Melbourne, 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. (2020). A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer. Cancer Epidemiology, Biomarkers and Prevention. Advance online publication. https://doi.org/10.1158/1055-9965.EPI-20-1176

@article{4434b8fb2d114744ab0be62d43231766,

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

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 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).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.",

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 Melbourne, {John L} and Figueiredo, {Jane C} and Newcomb, {Polly A} and Lindor, {Noralane M} and Graham Casey and Platz, {Elizabeth A} and {Le Marchand}, Loic and Ulrich, {Cornelia M} and Li, {Christopher I} and {van Duijnhoven}, {Fr{\"a}nzel J B} and Andrea Gsur and Peter Campbell and Victor 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 Hyeong-Rok Kim and Sun-Seog Kweon and Chan, {Andrew T} and Li Li and Wei Zheng and Bishop, {David T} 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 L} and Williams, {Ann C} and Relton, {Caroline L}",

note = "Copyright {\textcopyright}2020, American Association for Cancer Research.",

year = "2020",

month = dec,

day = "14",

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

language = "English",

journal = "Cancer Epidemiology, Biomarkers and Prevention",

issn = "1055-9965",

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

}

Nounu, A, Greenhough, A , Heesom, KJ , Richmond, RC, Zheng, J, Weinstein, SJ, Albanes, D, Baron, JA, Melbourne, JL, Figueiredo, JC, Newcomb, PA, Lindor, NM, Casey, G, Platz, EA, Le Marchand, L, Ulrich, CM, Li, CI, van Duijnhoven, FJB, Gsur, A, Campbell, P, 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, H-R, Kweon, S-S, 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 2020, 'A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer', Cancer Epidemiology, Biomarkers and Prevention. https://doi.org/10.1158/1055-9965.EPI-20-1176

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 - Melbourne, John L

AU - Figueiredo, Jane C

AU - Newcomb, Polly A

AU - Lindor, Noralane M

AU - Casey, Graham

AU - Platz, Elizabeth A

AU - Le Marchand, Loic

AU - Ulrich, Cornelia M

AU - Li, Christopher I

AU - van Duijnhoven, Fränzel J B

AU - Gsur, Andrea

AU - Campbell, Peter

AU - Moreno, Victor

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, David T

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 L

AU - Williams, Ann C

AU - Relton, Caroline L

PY - 2020/12/14

Y1 - 2020/12/14

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 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).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 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).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.

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

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

M3 - Article (Academic Journal)

C2 - 33318029

SN - 1055-9965

JO - Cancer Epidemiology, Biomarkers and Prevention

JF - Cancer Epidemiology, Biomarkers and Prevention

ER -

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

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Investigating the function of the BCL-3/Beta-canetin complex in promoting intestinal tumorigenesis and acquisition of therapeutic resistance

Cite this