PITX2 DNA Methylation as Biomarker for Individualized Risk Assessment of Prostate Cancer in Core Biopsies

Abstract

Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene is a strong predictor of the risk of biochemical recurrence in patients with prostate cancer (PCa) after radical prostatectomy. We investigate whether PITX2 methylation is feasible for individualized risk assessment in prostate core biopsies before surgery. A quantitative, methylation-specific real-time PCR was used to measure PITX2 in three cohorts: i) matched samples of neoplastic and nonneoplastic tissue from 24 patients with PCa, ii) a well-characterized cohort of 300 patients with PCa after radical prostatectomy, and iii) core biopsy specimens from 32 patients with PCa and 31 patients with benign prostatic disease. PITX2 methylation discriminated between neoplastic and nonneoplastic tissue in patients with PCa (P < 0.001). In the second cohort, PITX2 methylation significantly correlated with clinicopathologic parameters, and PITX2 hypermethylation predicted an increased risk of biochemical recurrence in univariate Cox proportional hazards regression analysis (hazard ratio, 1.77; P = 0.046) and Kaplan-Meier analysis (P = 0.043). In 753 prostate biopsies, 720 (95.6%) were applicable for analysis, rendering the assay feasible for diagnostic biopsies. PITX2 methylation was furthermore significantly increased in tumor-positive biopsies and strongly correlated with International Society of Urological Pathology (ISUP) grade groups. This study indicates that the PITX2 methylation assay is feasible in prostate biopsies and might add valuable prognostic information for risk assessment in a presurgical diagnostic setting.

Integrative clinical transcriptome analysis reveals TMPRSS2‐ERG dependency of prognostic biomarkers in prostate adenocarcinoma

“…A well-characterized prostatectomy cohort comprising 135 patients with known T2E-status (Supporting Information Table S2) diagnosed with PCa at the Institute of Pathology of the University Hospital of Bonn (Germany) was used as a second validation cohort. 23 The tissue microarray (TMA) cohort was established with ethics approval of the institutional review board of the University Hospital Bonn, which waived the need for written informed consent from the participants. 23 TMAs were constructed from formalin-fixed, paraffin-embedded archived tissue with up to five cores (diameter: 1 mm) of nonnecrotic tumor tissue per patient.…”

“…23 The tissue microarray (TMA) cohort was established with ethics approval of the institutional review board of the University Hospital Bonn, which waived the need for written informed consent from the participants. 23 TMAs were constructed from formalin-fixed, paraffin-embedded archived tissue with up to five cores (diameter: 1 mm) of nonnecrotic tumor tissue per patient. Antigen retrieval was achieved by ProTaqs IV Antigen-Enhancer (#401602392, Quartett) for RRM2 and ProTaqs IX Antigen-Enhancer (#401603692, Quartett) for TYMS.…”

Biomarker-based outcome prediction in prostate adenocarcinoma depends on theTMPRSS2-ERGstatus

“…A well-characterized prostatectomy cohort comprising 133 patients with known T2E-status (Supplementary Table 1) diagnosed with PCa at the Institute of Pathology of the University Hospital of Bonn (Germany) was used as a second validation cohort [24]. TMAs were constructed from formalin fixed, paraffin embedded archived tissue with up to 5 cores (diameter: 1 mm) of non-necrotic tumor tissue for each patient.…”

Application of omic technologies in cancer research

“…21 Hypermethylation of the paired-like homeodomain transcription factor 2 gene has been shown to be a prognostic indicator of disease recurrence in prostate cancer. 22 The Epigenome can also be influenced by altered chromatin regulation resulting from histone modifications. 23 Methylation of histones can alter the response and regulate the invasiveness of cells, which has been demonstrated in a study on the protein arginine methyltransferase 5 complexed with MEP50/WDR77.…”