Regulation of the tumor suppressor PLZF and prostate cancer prognosis.

Abstract

137 Background: PLZF ( ZBTB16) is an androgen-regulated tumor suppressor gene. Homozygous PLZF deletions are seen in a proportion of localized as well as castration-resistant prostate cancers (PC). Since PTEN has been shown to regulate PLZF expression in vitro, we hypothesized that PTEN status impacts PLZF expression in men with PC. We further hypothesized that low PLZF is associated with a poorer PC prognosis. Methods: We studied patients diagnosed with PC during prospective follow-up of the Health Professionals Follow-up Study (HPFS; n = 254) and the Physicians’ Health Study (PHS; n = 150). We performed whole transcriptome profiling of tumor specimens from cancer diagnosis and, in a subset of patients ( n = 253), a genomically-validated immunohistochemistry for PTEN. Patients were followed for metastases and PC-specific mortality (lethal cancer) after primary treatment for a median of 14 years. Univariable linear and multivariable logistic regression models for cancer outcomes, adjusted for age and calendar year, were used. For validation, the association of PTEN copy number variations and PLZF mRNA expression was assessed in The Cancer Genome Atlas (TCGA) primary PC cohort (n = 333). Results: Loss of PTEN protein expression was associated with lower PLZF expression (–0.72 standard deviations [SD]; 95% CI, –0.38 to –1.06; p < 0.001; HPFS and PHS cohorts), as were copy number variations in PTEN (TCGA cohort; –0.46 SD for deep deletions vs. diploid status; 95% CI, –0.13 to –0.79; p = 0.006) . PLZF expression did not differ significantly by Gleason grade in any cohort (all p > 0.09). In both the HPFS and PHS cohorts, the 25% of patients with the lowest PLZF expression were significantly more likely than those with higher expression to have progression to lethal cancer. This association was independent from Gleason grade, PTEN loss, and a signature of androgen receptor signaling (adjusted odds ratio for lethal cancer, 2.69; 95% CI, 1.18 to 6.14; p = 0.019). Conclusions: Loss of PTEN expression is associated with lower expression of PLZF amongst primary PC not exposed to ADT. In line with its action as a tumor suppressor, low PLZF expression is associated with lethal PC. Whether further suppression of PLZF with ADT worsens outcomes in advanced PC needs further study.