Journal Article

DKFZ-2024-01155

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Drew, D. A. ; Kim, A. E. ; Lin, Y. ; Qu, C. ; Morrison, J. ; Lewinger, J. P. ; Kawaguchi, E. ; Wang, J. ; Fu, Y. ; Zemlianskaia, N. ; Díez-Obrero, V. ; Bien, S. A. ; Dimou, N. ; Albanes, D. ; Baurley, J. W. ; Wu, A. H. ; Buchanan, D. D. ; Potter, J. D. ; Prentice, R. L. ; Harlid, S. ; Arndt, V.DKFZ* ; Barry, E. L. ; Berndt, S. I. ; Bouras, E. ; Brenner, H.DKFZ* ; Budiarto, A. ; Burnett-Hartman, A. ; Campbell, P. T. ; Carreras-Torres, R. ; Casey, G. ; Chang-Claude, J.DKFZ* ; Conti, D. V. ; Devall, M. A. M. ; Figueiredo, J. C. ; Gruber, S. B. ; Gsur, A. ; Gunter, M. J. ; Harrison, T. A. ; Hidaka, A. ; Hoffmeister, M.DKFZ* ; Huyghe, J. R. ; Jenkins, M. A. ; Jordahl, K. M. ; Kundaje, A. ; Le Marchand, L. ; Li, L. ; Lynch, B. M. ; Murphy, N. ; Nassir, R. ; Newcomb, P. A. ; Newton, C. C. ; Obón-Santacana, M. ; Ogino, S. ; Ose, J. ; Pai, R. K. ; Palmer, J. R. ; Papadimitriou, N. ; Pardamean, B. ; Pellatt, A. J. ; Peoples, A. R. ; Platz, E. A. ; Rennert, G. ; Ruiz-Narvaez, E. ; Sakoda, L. C. ; Scacheri, P. C. ; Schmit, S. L. ; Schoen, R. E. ; Stern, M. C. ; Su, Y.-R. ; Thomas, D. C. ; Tian, Y. ; Tsilidis, K. K. ; Ulrich, C. M. ; Um, C. Y. ; van Duijnhoven, F. J. B. ; Van Guelpen, B. ; White, E. ; Hsu, L. ; Moreno, V. ; Peters, U. ; Chan, A. T. ; Gauderman, W. J.

2024
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.adk3121

Abstract: Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Keyword(s): Humans (MeSH) ; Colorectal Neoplasms: genetics (MeSH) ; Colorectal Neoplasms: drug therapy (MeSH) ; Anti-Inflammatory Agents, Non-Steroidal: pharmacology (MeSH) ; Genome-Wide Association Study (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Aspirin: pharmacology (MeSH) ; Receptors, Prostaglandin E, EP4 Subtype: genetics (MeSH) ; Receptors, Prostaglandin E, EP4 Subtype: metabolism (MeSH) ; Male (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Female (MeSH) ; Case-Control Studies (MeSH) ; Middle Aged (MeSH) ; Genetic Loci (MeSH) ; Aged (MeSH) ; Anti-Inflammatory Agents, Non-Steroidal ; Aspirin ; Receptors, Prostaglandin E, EP4 Subtype ; PTGER4 protein, human

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)
2. Präventive Onkologie (C120)
3. DKTK HD zentral (HD01)
4. C020 Epidemiologie von Krebs (C020)
5. C071 Cancer Survivorship (C071)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2024

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