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A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.

ABSTRACT: The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73-100) and 65% (95% CI 52-78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).

SUBMITTER: Castelo-Branco P

PROVIDER: S-EPMC5295385 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.

Castelo-Branco Pedro P Leão Ricardo R Lipman Tatiana T Campbell Brittany B Lee Donghyun D Price Aryeh A Zhang Cindy C Heidari Abolfazl A Stephens Derek D Boerno Stefan S Coelho Hugo H Gomes Ana A Domingos Celia C Apolonio Joana D JD Schäfer Georg G Bristow Robert G RG Schweiger Michal R MR Hamilton Robert R Zlotta Alexandre A Figueiredo Arnaldo A Klocker Helmut H Sültmann Holger H Tabori Uri U

Oncotarget 20160901 36

The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed ...[more]

PMID: 27437772

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Project description:Purpose: Available tools for prostate cancer (PC) diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE~miR-452~miR-224 genomic locus. Experimental design: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 non-malignant and 281 PC tissue samples. GABRE promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 non-malignant, 293 PC (radical prostatectomy (RP) cohort 1) and 198 PC tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE methylation was evaluated by ROC, Kaplan-Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of post-transfection transcriptional profiling data. Results: GABRE~miR-452~miR-224 was significantly downregulated in PC compared to non-malignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC=0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular motility. Finally, in uni- and multivariate analyses, high GABRE promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2. Conclusion: The GABRE~miR-452~miR-224 locus is downregulated and hypermethylated in PC and is a new promising epigenetic candidate biomarker for PC diagnosis and prognosis. Tumor suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two PC cell lines, suggesting that epigenetic silencing of GABRE~miR-452~miR-224 may be selected for in PC. Affymetrix GeneChip Human Gene 1.0 ST Arrays were used for whole-genome transcriptional profiling of DU145 and PC3 cells at 48 hours post-transfection with either miR-224, miR-452, or scrambled miRNA mimics, or untransfected. All experiments were performed in duplicate. Transcript expression levels were determined after RMA16 normalization in GeneSpringGX 11.0 software (Agilent). PC3 and DU145 arrays were normalized separately. DU145 48 t Scr2a were excluded from the study because of bad performance of this microarray.

Project description:Background: Nowadays, predictions of biochemical recurrence (BCR) in localized prostate cancer (PCa) patients after radical prostatectomy (RP) are mainly based on clinical parameters with a low predictive accuracy. Given the critical role of apoptosis in PCa occurrence and progression, we aimed to establish a novel predictive model based on apoptosis-related gene signature and clinicopathological parameters that can improve risk stratification for BCR and assist in clinical decision-making. Methods: Expression data and corresponding clinical information were obtained from four public cohorts, one from The Cancer Genome Atlas (TCGA) dataset and three from the Gene Expression Omnibus (GEO) dataset. Weighted gene co-expression network analysis (WGCNA) was performed to identify candidate modules closely correlated to BCR, and univariate and multivariate Cox regression analyses were utilized to build the gene signature. Time-dependent receiver operating curve (ROC) and Kaplan-Meier (KM) survival analysis were used to assess the prognostic value. Finally, we analyzed the expression of genes in the signature and validated the results using quantitative real-time PCR (qRT-PCR). Results: The novel gene signature we established exhibited a high prognostic value and was able to act as an independent risk factor for BCR [Training set: P < 0.001, hazard ratio (HR) = 7.826; Validation set I: P = 0.006, HR = 2.655; Validation set II: P = 0.003, HR = 4.175; Validation set III: P < 0.001, HR = 3.008]. Nomogram based on the gene signature and clinical parameters was capable of distinguishing high-risk BCR patients. Additionally, functional enrichment analysis showed several enriched pathways and biological processes, which might help reveal the underlying mechanism. The expression results of qRT-PCR were consistent with TCGA results. Conclusion: The apoptosis-related gene signature could serve as a powerful predictor and risk factor for BCR in localized PCa patients after RP.

Dataset Information

A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.

Publications

A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.

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