Purpose: Pharmacoepidemiology studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that aspirin induces transcriptional changes in tumors or normal prostate tissue.
Methods: We analyzed the prostatic transcriptome from men diagnosed with prostate cancer during follow-up of the Physicians' Health Study 1 (PHS, n = 149), initially a randomized controlled trial of aspirin. Aspirin target genes were identified through systematic literature review and a drug target database. We compared target gene expression according to regular aspirin use at cancer diagnosis and used whole-transcriptome gene set enrichment analysis to identify gene sets associated with aspirin use. Results were validated in the Health Professionals Follow-up Study (HPFS, n = 254) and in Connectivity Map.
Results: Of 12 target genes identified from prior studies and 540 genes from the drug target database, none were associated with aspirin use. Twenty-one gene sets were enriched in tumor tissue of aspirin users, 18 of which were clustered around ribosome function and translation. These gene sets were associated with exposure to cyclooxygenase inhibitors in Connectivity Map. Their association with cancer prognosis was U-shaped in both cohorts. No gene sets were enriched in normal tissue. In HPFS, neither the target genes nor the gene sets were associated with aspirin use.
Conclusions: Regular aspirin use may affect ribosome function in prostate tumors. Other putative target genes had similar expression in tumors from aspirin users and non-users. If results are corroborated by experimental studies, a potential benefit of aspirin may be limited to a subset of prostate cancer patients.
Keywords: Aspirin; Prognosis; Prostate cancer; Ribosome; Transcriptome.
Conflict of interest statement
Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.Eur Urol. 2017 Nov;72(5):821-827. doi: 10.1016/j.eururo.2017.01.044. Epub 2017 Feb 8. Eur Urol. 2017. PMID: 28189429 Clinical Trial.
Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.EBioMedicine. 2015 Jul 29;2(9):1133-44. doi: 10.1016/j.ebiom.2015.07.017. eCollection 2015 Sep. EBioMedicine. 2015. PMID: 26501111 Free PMC article.
A Prospective Study of Aspirin Use and Prostate Cancer Risk by TMPRSS2:ERG Status.Cancer Epidemiol Biomarkers Prev. 2018 Oct;27(10):1231-1233. doi: 10.1158/1055-9965.EPI-18-0510. Epub 2018 Aug 14. Cancer Epidemiol Biomarkers Prev. 2018. PMID: 30108097 Free PMC article.
Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis.BMC Med. 2014 Mar 28;12:55. doi: 10.1186/1741-7015-12-55. BMC Med. 2014. PMID: 24678716 Free PMC article. Review.
Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews.Health Technol Assess. 2013 Sep;17(43):1-253. doi: 10.3310/hta17430. Health Technol Assess. 2013. PMID: 24074752 Free PMC article. Review.
- U01 CA167552/National Cancer Institute
- P50 CA090381/CA/NCI NIH HHS/United States
- HL34595/National Heart, Lung, and Blood Institute
- R01 HL034595/HL/NHLBI NIH HHS/United States
- U01 CA167552/CA/NCI NIH HHS/United States
- P30 CA008748/CA/NCI NIH HHS/United States
- P30 CA008748/National Cancer Institute
- HL26490/National Heart, Lung, and Blood Institute
- 5P50 CA090381/National Cancer Institute
- R01 HL026490/HL/NHLBI NIH HHS/United States
- Young Investigator Award/Prostate Cancer Foundation
- CA34944/National Cancer Institute
- R01 CA040360/CA/NCI NIH HHS/United States
- R01 CA097193/CA/NCI NIH HHS/United States
- R01 CA034944/CA/NCI NIH HHS/United States
- CA097193/National Cancer Institute