Regular aspirin use and gene expression profiles in prostate cancer patients
Pharmacoepidemiology studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that aspirin induces transcriptional changes in tumors or normal prostate tissue.
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.
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.
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.
KeywordsAspirin Transcriptome Ribosome Prognosis Prostate cancer
We would like to thank the participants and staff of the Health Professionals Follow-up Study and the Physicians’ Health Study for their valuable contributions. In particular, we would like to recognize the contributions of Liza Gazeeva, Siobhan Saint-Surin, Robert Sheahan, and Betsy Frost-Hawes. We would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
The Health Professionals Follow-up Study was supported by the National Institutes of Health [U01 CA167552]. The Physicians’ Health Study was supported by the National Institutes of Health [CA097193, CA34944, CA40360, HL26490, HL34595]. This research was funded in part by the Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence program in Prostate Cancer [5P50 CA090381] and the NIH/NCI Cancer Center Support Grant [P30 CA008748]. K.H.S., J.R.R., and L.A.M. are Prostate Cancer Foundation Young Investigators.
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Conflict of interest
The authors declare that they have no conflict of interests.
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