Abstract 4740: Loss of the tumor suppressor zinc finger protein-36 and risk of lethal prostate cancer

Abstract

Abstract Background. Biomarkers are needed to complement current clinicopathologic variables towards distinguishing prostate tumors that are likely to be metastatic from those that are indolent. We previously used a bioinformatic analytical approach to identify ZFP36, also known as Tristetraprolin (TTP), as a tumor suppressor in the NFκB pathway. The current study aims to evaluate the prognostic potential of tumor mRNA expression of ZFP36. Methods. Our primary analysis leveraged data from a case-control study nested in the Health Professionals Follow-up Study and Physicians’ Health Study. Gene expression for ZFP36 was quantified from archival surgical tumor tissue using Affymetrix Human Gene 1.0 ST microarrays. Cases (n=113) were men who died of prostate cancer or developed metastatic disease, and controls (n=291) were men who lived at least 8 years after diagnosis and remained metastasis free. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs) for a subset of the men (n=257). Results. Mean ZFP36 expression was significantly lower in the cases compared to the controls (p<0.001), and the crude odds ratio (OR) for lethal disease comparing those with low ZFP36 expression (below the lower quartile) to those with high ZFP36 expression (greater than or equal to the lower quartile) was 3.52 (95% CI: 2.18-5.69; p<0.001). The association persisted with adjustment for Gleason category, age at diagnosis, and clinical stage, with an adjusted OR of 1.93 (95% CI: 1.07-3.49; p=0.03). When modeled as a continuous variable in a logistic regression for prognosis, ZFP36 improved the AUC of the clinical factor model (Gleason, age, and clinical stage) from 0.83 (95% CI: 0.79-0.88) to 0.85 (95% CI: 0.81-0.89; p=0.10 for improvement). Among the patients with available PTEN staining, independent effects of ZFP36 and PTEN loss were observed. In the logistic regression on lethal disease with both variables included, PTEN negativity conferred an OR of 2.10 (95% CI: 1.11-3.93; p=0.02) and low ZFP36 produced an OR of 2.34 (95% CI: 1.24-4.36; p=0.01). Taken together, we observed an OR of 4.90 (95% CI: 2.05-11.72) comparing patients with PTEN negativity and low ZFP36 to those with PTEN staining present and high ZFP36. Conclusions. Loss of the tumor suppressor ZFP36 is prognostic for metastatic or lethal prostate cancer. Combining information on ZFP36 with measurements from other mechanistic pathways, such as PTEN, may lead to highly accurate models. Citation Format: Travis Gerke, Daniela Börnigen, Himisha Beltran, Svitlana Tyekucheva, Curtis Huttenhower, Gwo-Shu Lee, Bruce Trock, Lorelei Mucci, Christopher Sweeney. Loss of the tumor suppressor zinc finger protein-36 and risk of lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4740. doi:10.1158/1538-7445.AM2017-4740