PITX3 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients after radical prostatectomy

Abstract

BackgroundMolecular biomarkers that might help to distinguish between more aggressive and clinically insignificant prostate cancers (PCa) are still urgently needed. Aberrant DNA methylation as a common molecular alteration in PCa seems to be a promising source for such biomarkers. In this study, PITX3 DNA methylation (mPITX3) and its potential role as a prognostic biomarker were investigated. Furthermore, mPITX3 was analyzed in combination with the established PCa methylation biomarker PITX2 (mPITX2).MethodsmPITX3 and mPITX2 were assessed by a quantitative real-time PCR and by means of the Infinium HumanMethylation450 BeadChip. BeadChip data were obtained from The Cancer Genome Atlas (TCGA) Research Network. DNA methylation differences between normal adjacent, benign hyperplastic, and carcinomatous prostate tissues were examined in the TCGA dataset as well as in prostatectomy specimens from the University Hospital Bonn. Retrospective analyses of biochemical recurrence (BCR) were conducted in a training cohort (n = 498) from the TCGA and an independent validation cohort (n = 300) from the University Hospital Bonn. All patients received radical prostatectomy.ResultsIn PCa tissue, mPITX3 was increased significantly compared to normal and benign hyperplastic tissue. In univariate Cox proportional hazards analyses, mPITX3 showed a significant prognostic value for BCR (training cohort: hazard ratio (HR) = 1.83 (95 % CI 1.07–3.11), p = 0.027; validation cohort: HR = 2.56 (95 % CI 1.44–4.54), p = 0.001). A combined evaluation with PITX2 methylation further revealed that hypermethylation of a single PITX gene member (either PITX2 or PITX3) identifies an intermediate risk group.ConclusionsPITX3 DNA methylation alone and in combination with PITX2 is a promising biomarker for the risk stratification of PCa patients and adds relevant prognostic information to common clinically implemented parameters. Further studies are required to determine whether the results are transferable to a biopsy-based patient cohort. Trial registration: Patients for this unregistered study were enrolled retrospectively.

PITX3 DNA methylation is an independent predictor of overall survival in patients with head and neck squamous cell carcinoma

“…While this model cannot serve as a model for HNSCC tumorigenesis, it is an interesting finding and possibly allows for the implication of PITX3 alteration being an early event in cancer development. This would be in line with the results of Holmes et al, who were able to show that PITX3 methylation is a strong prognostic marker for biochemical recurrence in localized prostate cancer [ 22 ].…”

“…For the training cohort, quantitative PITX3 methylation analysis was performed by means of quantitative real-time PCR (qPCR) with primers and probes as previously described [ 22 ]. The analytical performance of the qPCR assay has been characterized earlier [ 22 ].…”

“…1 Genomic organization and assay position. Genomic organization of the PITX3 gene and locations of the PITX3 qPCR assay [ 22 ] and the Infinium HumanMethylation450 BeadChip bead cg20023259. The information was obtained from Ensembl Homo sapiens version GRCh38.p7 …”

“…It has been found to be hypermethylated in breast cancer tumors [ 21 ]. Recently, Holmes et al reported that PITX3 promoter methylation is strongly associated with biochemical recurrence-free survival in prostate cancer patients [ 22 ].…”

Prognostic value and potential function of splicing events in prostate adenocarcinoma

“…tROC analysis indicated that in patients with PRAD, the AUC of PI-ES was 0.7403 for predicting the cancer status after five years. In addition, the HR of PI-ES for tumor recurrence was 4.097 (95% CI: 2.439-6.881, P=9.77×10 −8 ) according to univariate Cox analysis and 2.599 (95% CI: 1.329-5.084, P=0.005) according to multivariate Cox analysis, which were better than previously reported values focusing on only a single indicator, including programmed death-1 receptor methylation ( 44 ), pituitary homeobox 3 methylation ( 45 ) and cysteine dioxygenase 1 promoter methylation ( 46 ).…”