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A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer
A. Nounu, A. Greenhough, KJ. Heesom, RC. Richmond, J. Zheng, SJ. Weinstein, D. Albanes, JA. Baron, JL. Hopper, JC. Figueiredo, PA. Newcomb, NM. Lindor, G. Casey, EA. Platz, L. Le Marchand, CM. Ulrich, CI. Li, FJB. van Duijnhoven, A. Gsur, PT....
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
Grant support
R01 CA067941
NCI NIH HHS - United States
U01 HG004438
NHGRI NIH HHS - United States
U01 HG004446
NHGRI NIH HHS - United States
U10 CA037429
NCI NIH HHS - United States
K05 CA154337
NCI NIH HHS - United States
U01 CA164930
NCI NIH HHS - United States
P30 CA076292
NCI NIH HHS - United States
R01 CA042182
NCI NIH HHS - United States
P50 CA127003
NCI NIH HHS - United States
U01 CA067941
NCI NIH HHS - United States
R01 CA059045
NCI NIH HHS - United States
HHSN268201100001I
NHLBI NIH HHS - United States
R01 CA197350
NCI NIH HHS - United States
R01 CA076366
NCI NIH HHS - United States
R35 CA197735
NCI NIH HHS - United States
R01 CA072520
NCI NIH HHS - United States
P01 CA087969
NCI NIH HHS - United States
P30 CA015704
NCI NIH HHS - United States
HHSN268201100004I
NHLBI NIH HHS - United States
P30 CA006973
NCI NIH HHS - United States
U24 CA074783
NCI NIH HHS - United States
P01 CA055075
NCI NIH HHS - United States
S10 OD028685
NIH HHS - United States
R01 CA151993
NCI NIH HHS - United States
HHSN268201100046C
NHLBI NIH HHS - United States
P30 DK034987
NIDDK NIH HHS - United States
R01 CA048998
NCI NIH HHS - United States
U01 CA137088
NCI NIH HHS - United States
11975
Cancer Research UK - United Kingdom
R01 CA189184
NCI NIH HHS - United States
U01 CA167552
NCI NIH HHS - United States
HHSN268201100003C
WHI NIH HHS - United States
MC_UU_12013_2
Medical Research Council - United Kingdom
Z01 CP010200
Intramural NIH HHS - United States
U24 CA074794
NCI NIH HHS - United States
R01 CA066635
NCI NIH HHS - United States
R21 CA191312
NCI NIH HHS - United States
U01 CA206110
NCI NIH HHS - United States
HHSN268201200008C
NHLBI NIH HHS - United States
C18281/A19169
Cancer Research UK - United Kingdom
R01 CA137178
NCI NIH HHS - United States
U01 CA074794
NCI NIH HHS - United States
P30 CA008748
NCI NIH HHS - United States
U01 CA167551
NCI NIH HHS - United States
P30 CA014089
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R01 CA081488
NCI NIH HHS - United States
HHSN271201100004C
NIA NIH HHS - United States
R01 CA201407
NCI NIH HHS - United States
R01 CA063464
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P01 CA033619
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U01 CA086308
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UM1 CA186107
NCI NIH HHS - United States
HHSN268201100002C
WHI NIH HHS - United States
R01 CA207371
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R03 CA153323
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T32 ES013678
NIEHS NIH HHS - United States
R01 CA136726
NCI NIH HHS - United States
P30 CA016058
NCI NIH HHS - United States
UM1 CA167552
NCI NIH HHS - United States
K05 CA152715
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U01 CA122839
NCI NIH HHS - United States
Wellcome Trust - United Kingdom
HHSN268201100003I
NHLBI NIH HHS - United States
HHSN268201100002I
NHLBI NIH HHS - United States
U01 CA074783
NCI NIH HHS - United States
U01 CA084968
NCI NIH HHS - United States
KL2 TR000421
NCATS NIH HHS - United States
MR/R017247/1
Medical Research Council - United Kingdom
UM1 CA182883
NCI NIH HHS - United States
K07 CA190673
NCI NIH HHS - United States
HHSN268201200008I
NHLBI NIH HHS - United States
217487/Z/19/Z
Wellcome Trust - United Kingdom
U01 CA164973
NCI NIH HHS - United States
R37 CA054281
NCI NIH HHS - United States
HHSN268201100001C
WHI NIH HHS - United States
HHSN268201100004C
WHI NIH HHS - United States
R01 CA097325
NCI NIH HHS - United States
HHSN268201700006C
NHLBI NIH HHS - United States
U19 CA148107
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U01 AG018033
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NLK
Free Medical Journals
from 1991 to 1 year ago
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from 1991 to 12 months ago
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Open Access Digital Library
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- MeSH
- Aspirin pharmacology therapeutic use MeSH
- Colorectal Neoplasms drug therapy MeSH
- Humans MeSH
- Mendelian Randomization Analysis methods MeSH
- Proteomics methods MeSH
- Risk Factors MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
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.
Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia
Broad Institute of Harvard and MIT Cambridge Massachusetts
Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia
Center for Public Health Genomics University of Virginia Charlottesville Virginia
CIBER Epidemiología y Salud Pública Madrid Spain
Clalit National Cancer Control Center Haifa Israel
Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden
Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain
Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland
Department of Epidemiology University of Washington School of Public Health Seattle Washington
Department of Family Medicine University of Virginia Charlottesville Virginia
Department of General Surgery University Hospital Rostock Rostock Germany
Department of Health Science Research Mayo Clinic Scottsdale Arizona
Department of Internal Medicine University of Utah Salt Lake City Utah
Department of Medicine Memorial Sloan Kettering Cancer Center New York New York
Department of Medicine University of North Carolina School of Medicine Chapel Hill North Carolina
Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
Department of Preventive Medicine Chonnam National University Medical School Gwangju Korea
Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom
Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden
Department of Surgery Chonnam National University Hwasun Hospital and Medical School Hwasun Korea
Department of Surgical Sciences Uppsala University Uppsala Sweden
Discipline of Genetics Memorial University of Newfoundland St John's Canada
Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany
Division of Human Nutrition and Health Wageningen University and Research Wageningen the Netherlands
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Division of Research Kaiser Permanente Northern California Oakland California
Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic
Genetic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville Victoria Australia
German Cancer Consortium Heidelberg Germany
Institute of Cancer Research Department of Medicine 1 Medical University Vienna Vienna Austria
Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
Institute of Medical Biometry and Informatics University of Heidelberg Heidelberg Germany
Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun Korea
Leeds Institute of Cancer and Pathology University of Leeds Leeds United Kingdom
ONCOBEL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain
Proteomics Facility Faculty of Life Sciences University of Bristol Bristol United Kingdom
Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington
Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel
School of Cellular and Molecular Medicine University of Bristol Bristol United Kingdom
School of Public Health University of Washington Seattle Washington
University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany
University of Hawaii Cancer Center Honolulu Hawaii
University of Southern California Preventative Medicine Los Angeles California
Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden
References provided by Crossref.org
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