Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis

Abstract

Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort (n = 292), we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples (p < 0.001) with an AUC (area under the curve) of 0.908 by receiver operating characteristics (ROC) curve analysis. Moreover, significant TFF3 promoter hypomethylation (p ≤ 0.010) as well as overexpression (p < 0.001) was found in PC samples from another large independent patient sample set (498 PC vs. 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor (ERG) expression (p < 0.001), as well as with high Gleason score (p < 0.001), advanced pathological T-stage (p < 0.001), and prostate-specific antigen (PSA) recurrence after RP (p = 0.013; univariate Cox regression analysis). There were no significant associations between TFF3 promoter methylation levels, ERG status, or PSA recurrence in these RP cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of TFF3 promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of TFF3 promoter methylation and transcriptional expression in PC to date.

Dietary Compounds as Epigenetic Modulating Agents in Cancer

“…For instance, LINE-1 gene hypomethylation is associated with different clinical-pathological characteristics in lung cancer; early carcinogenesis in breast cancer, and metastasis in colorectal adenocarcinoma (Estécio et al, 2007; Hur et al, 2014; Park et al, 2014; Imperatori et al, 2017). On the other hand, hypomethylation of specific genes like TTF-3, MUC4, and CT45 frequently occur in prostate, pancreatic and ovarian cancers (Zhu et al, 2011; Zhang W. et al, 2015; Haldrup et al, 2017; Nørgaard et al, 2017). The hypermethylation of RASSF1A gene has been identified as a diagnostic marker in lung cancer, whereas it contributes to increased mortality in women with breast cancer.…”

Advances in Prognostic Methylation Biomarkers for Prostate Cancer

“…SERPINB5 and AIM1 , the only markers found to have significant associations with progression [ 95 ] and overall survival [ 85 ] have only been investigated in two small independent studies each thus far, and require further validation in larger cohorts. And finally, new candidate genes from different biological pathways have been explored recently (e.g., PD1− , PD-L1 , CDO1 , TFF3 , ZNF660 ) [ 108 , 109 , 110 , 111 , 112 ] and also require further validation.…”

Advances in Prognostic Methylation Biomarkers for Prostate Cancer

“…And finally, new candidate genes from different biological pathways have been explored recently (e.g. PD-1, PD-L1, CDO1, TFF3, ZNF660) [108][109][110][111][112] and also require further validation.…”