Stopsack Konrad H, Ebot Ericka M, Downer Mary K, Gerke Travis A, Rider Jennifer R, Kantoff Philip W, Mucci Lorelei A
Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
Cancer Causes Control. 2018 Aug;29(8):775-784. doi: 10.1007/s10552-018-1049-5. Epub 2018 Jun 18.
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.
药物流行病学研究表明阿司匹林对前列腺癌具有预后益处。我们推测阿司匹林可诱导肿瘤或正常前列腺组织发生转录变化。
我们分析了在医师健康研究1（PHS，n = 149）随访期间被诊断为前列腺癌的男性的前列腺转录组，该研究最初是一项阿司匹林随机对照试验。通过系统的文献综述和药物靶点数据库确定阿司匹林的靶基因。我们根据癌症诊断时是否规律使用阿司匹林比较了靶基因表达，并使用全转录组基因集富集分析来识别与阿司匹林使用相关的基因集。结果在健康专业人员随访研究（HPFS，n = 254）和连通性图谱中得到验证。
在先前研究确定的12个靶基因和药物靶点数据库中的540个基因中，没有一个与阿司匹林使用相关。21个基因集在阿司匹林使用者的肿瘤组织中富集，其中18个围绕核糖体功能和翻译聚集。这些基因集在连通性图谱中与环氧化酶抑制剂的暴露相关。它们与癌症预后的关联在两个队列中均呈U形。正常组织中没有基因集富集。在HPFS中，靶基因和基因集均与阿司匹林使用无关。
规律使用阿司匹林可能会影响前列腺肿瘤中的核糖体功能。其他假定的靶基因在阿司匹林使用者和非使用者的肿瘤中表达相似。如果实验研究证实了这些结果，阿司匹林的潜在益处可能仅限于一部分前列腺癌患者。
