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Epigenetic silencing of MEIS2 in prostate cancer recurrence.
Nørgaard, Maibritt; Haldrup, Christa; Bjerre, Marianne Trier; Høyer, Søren; Ulhøi, Benedicte; Borre, Michael; Sørensen, Karina D.
Affiliation
  • Nørgaard M; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Haldrup C; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Bjerre MT; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Høyer S; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Ulhøi B; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Borre M; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Sørensen KD; Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
Clin Epigenetics ; 11(1): 147, 2019 10 22.
Article in En | MEDLINE | ID: mdl-31640805
BACKGROUND: Current diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, resulting in overdiagnosis and overtreatment of clinically insignificant tumors. Thus, to improve the management of PC, novel biomarkers are urgently needed. RESULTS: In this study, we integrated genome-wide methylome (Illumina 450K DNA methylation array (450K)) and RNA sequencing (RNAseq) data performed in a discovery set of 27 PC and 15 adjacent normal (AN) prostate tissue samples to identify candidate driver genes involved in PC development and/or progression. We found significant enrichment for homeobox genes among the most aberrantly methylated and transcriptionally dysregulated genes in PC. Specifically, homeobox gene MEIS2 (Myeloid Ecotropic viral Insertion Site 2) was significantly hypermethylated (p < 0.0001, Mann-Whitney test) and transcriptionally downregulated (p < 0.0001, Mann-Whitney test) in PC compared to non-malignant prostate tissue in our discovery sample set, which was also confirmed in an independent validation set including > 500 PC and AN tissue samples in total (TCGA cohort analyzed by 450K and RNAseq). Furthermore, in three independent radical prostatectomy (RP) cohorts (n > 700 patients in total), low MEIS2 transcriptional expression was significantly associated with poor biochemical recurrence (BCR) free survival (p = 0.0084, 0.0001, and 0.0191, respectively; log-rank test). Next, we analyzed another RP cohort consisting of > 200 PC, AN, and benign prostatic hyperplasia (BPH) samples by quantitative methylation-specific PCR (qMSP) and found that MEIS2 was significantly hypermethylated (p < 0.0001, Mann-Whitney test) in PC compared to non-malignant prostate tissue samples (AN and BPH) with an AUC > 0.84. Moreover, in this cohort, aberrant MEIS2 hypermethylation was significantly associated with post-operative BCR (p = 0.0068, log-rank test), which was subsequently confirmed (p = 0.0067; log-rank test) in the independent TCGA validation cohort (497 RP patients; 450K data). CONCLUSIONS: To the best of our knowledge, this is the first study to investigate, demonstrate, and independently validate a prognostic biomarker potential for MEIS2 at the transcriptional expression level and at the DNA methylation level in PC.
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Full text: 1 Database: MEDLINE Main subject: Prostatic Neoplasms / Transcription Factors / Down-Regulation / Homeodomain Proteins / DNA Methylation / Neoplasm Recurrence, Local Type of study: Prognostic_studies Limits: Aged / Humans / Male / Middle aged Language: En Journal: Clin Epigenetics Year: 2019 Type: Article Affiliation country: Denmark

Full text: 1 Database: MEDLINE Main subject: Prostatic Neoplasms / Transcription Factors / Down-Regulation / Homeodomain Proteins / DNA Methylation / Neoplasm Recurrence, Local Type of study: Prognostic_studies Limits: Aged / Humans / Male / Middle aged Language: En Journal: Clin Epigenetics Year: 2019 Type: Article Affiliation country: Denmark