Regular aspirin use and gene expression profiles in prostate cancer patients

Abstract

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.

Fig. 1

Enrichment Map of 21 gene sets according to the Gene Ontology (GO) biological process database that were enriched at a false-discovery rate (FDR) q < 0.25 when comparing tumor tissue from aspirin users to non-users in the Physicians’ Health Study 1 (PHS). Nodes represent gene sets and their size the number of genes. Lines and their thickness indicate overlap between gene sets.