DNA Methylation Signatures for Prediction of Biochemical Recurrence After Radical Prostatectomy of Clinically Localized Prostate Cancer

Haldrup, Christa; Mundbjerg, Kamilla; Vestergaard, Else Marie; Lamy, Philippe; Wild, Peter J.; Schulz, Wolfgang A.; Arsov, Christian; Visakorpi, Tapio; Borre, Michael; Høyer, Søren; Ørntoft, Torben F.; Sørensen, Karina Dalsgaard

doi:10.1200/jco.2012.47.1847

Cited by 119 publications

(173 citation statements)

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“…A recent European study on over 400 total samples reported 6 novel candidate DNA methylation markers for PCa; 3 of these markers, C1orf114, AOX1, and HAPLN3, were independent predictors of time to biochemical recurrence after radical prostatectomy. 41 Additional emerging candidate markers for prognosis were also published. 42,43 Cross validation of these potential prognostic markers in various cohorts will be important to confirm truly useful methylation markers for clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Methylation profiling identified novel differentially methylated markers includingOPCMLandFLRT2in prostate cancer

Davison

et al. 2016

Epigenetics

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To develop new methods to distinguish indolent from aggressive prostate cancers (PCa), we utilized comprehensive high-throughput array-based relative methylation (CHARM) assay to identify differentially methylated regions (DMRs) throughout the genome, including both CpG island (CGI) and non-CGI regions in PCa patients based on Gleason grade. Initially, 26 samples, including 8 each of low [Gleason score (GS) 6] and high (GS 7) grade PCa samples and 10 matched normal prostate tissues, were analyzed as a discovery cohort. We identified 3,567 DMRs between normal and cancer tissues, and 913 DMRs distinguishing low from high-grade cancers. Most of these DMRs were located at CGI shores. The top 5 candidate DMRs from the low vs. high Gleason comparison, including OPCML, ELAVL2, EXT1, IRX5, and FLRT2, were validated by pyrosequencing using the discovery cohort. OPCML and FLRT2 were further validated in an independent cohort consisting of 20 low-Gleason and 33 high-Gleason tissues. We then compared patients with biochemical recurrence (nD70) vs. those without (nD86) in a third cohort, and they showed no difference in methylation at these DMR loci. When GS 3C4 cases and GS 4C3 cases were compared, OPCML-DMR methylation showed a trend of lower methylation in the recurrence group (nD30) than in the no-recurrence (nD52) group. We conclude that whole-genome methylation profiling with CHARM revealed distinct patterns of differential DNA methylation between normal prostate and PCa tissues, as well as between different risk groups of PCa as defined by Gleason scores. A panel of selected DMRs may serve as novel surrogate biomarkers for Gleason score in PCa.

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Section: Discussionmentioning

confidence: 99%

Methylation profiling identified novel differentially methylated markers includingOPCMLandFLRT2in prostate cancer

Davison

et al. 2016

Epigenetics

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“…2A). Two methylation microarray datasets (29), including a total of 30 nonmalignant and 30 prostate cancer tissue samples, showed significant (P < 0.001) promoter hypermethylation in prostate cancer samples (Fig. 2B).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…One microgram of DNA was bisulfite converted, whole genome amplified, and applied to Illumina's Infinium HumanMethylation27 Beadchip v1.2 (29) or HumanMethylation450 BeadChip (Strand and colleagues, unpublished) according to protocols from the manufacturer.…”

Section: Dna Extraction and Methylation Analysismentioning

confidence: 99%

Hypermethylation of theGABRE∼miR-452∼miR-224Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

Kristensen

Haldrup

Strand

et al. 2014

Clinical Cancer Research

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Purpose: Available tools for prostate cancer 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 nonmalignant and 281 prostate cancer tissue samples. GABRE$miR-452$miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE$miR-452$miR-224 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 posttransfection transcriptional profiling data.Results: GABRE$miR-452$miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC ¼ 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 adhesion and motility. Finally, in uni-and multivariate analyses, high GABRE$miR-452$miR-224 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 prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE$miR-452$miR-224 may be selected for in prostate cancer. Clin Cancer Res; 20(8); 2169-81. Ó2014 AACR.

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“…Especially in PCa, recent studies have indicated that this particular epigenetic alteration may be associated with the advanced metastatic stage. Several genes, including those that encode glutathione S-transferase π 1 (GSTP1), adenomatous polyposis coli (APC), Ras association domain-containing protein 1 (RASSF1A) and prostaglandinendoperoxide synthase 2 (PTGS2), have been demonstrated to be hypermethylated in PCa, but not in the normal prostate tissues (6,13,14). Similarly, many hypomethylated genes have been identified and demonstrated to be associated with the recurrent status of PCa patients (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Aberrant hypomethylation-mediated CD147 overexpression promotes aggressive tumor progression in human prostate cancer

Liang

et al. 2015

Oncology Reports

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Abstract. Our previous study revealed the potential role of CD147 in human prostate cancer (PCa). Here, we investigated the CD147 promoter methylation status and the correlation with tumorigenicity in human PCa. CD147 mRNA and protein expression levels were both significantly higher in the 4 PCa cell lines, than in the 2 non-tumorigenic benign human prostatic epithelial cell lines (all P<0.01). We showed hypomethylation of promoter regions of CD147 in PCa cell lines with significant CD147 expression as compared to non-tumorigenic benign human prostatic epithelial cell lines slowly expressing CD147. Additionally, the treatment of methylated cell lines with 5-aza-2'-deoxycytidine increased CD147 expression significantly in low-expressing cell lines and also activated the expression of matrix metalloproteinase (MMP)-2, which may be one of the most important downstream targets of CD147. Furthermore, PCa tissues displayed decreased DNA methylation in the promoter region of CD147 compared to the corresponding non-cancerous prostate tissues, and methylation intensity correlated inversely with the CD147 mRNA levels. There was a significant negative correlation between CD147 mRNA levels and the number of methylated sites in PCa tissues (r=-0.467, P<0.01). In conclusion, our data offer convincing evidence for the first time that the DNA promoter hypomethylation of CD147 may be one of the regulatory mechanisms involved in the cancer-related overexpression of CD147 and may play a crucial role in the tumorigenesis of PCa.

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DNA Methylation Signatures for Prediction of Biochemical Recurrence After Radical Prostatectomy of Clinically Localized Prostate Cancer

Abstract: We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.

Cited by 119 publications

References 30 publications

Methylation profiling identified novel differentially methylated markers includingOPCMLandFLRT2in prostate cancer

Methylation profiling identified novel differentially methylated markers includingOPCMLandFLRT2in prostate cancer

Hypermethylation of theGABRE∼miR-452∼miR-224Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

Aberrant hypomethylation-mediated CD147 overexpression promotes aggressive tumor progression in human prostate cancer

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