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

Emily Eva Holmes,Jörn Dietrich,Diane Goltz,Dimo Dietrich,Sebastian Meller,Barbara Uhl,Maria Jung,Jörg Ellinger,Verena Sailer,Glen Kristiansen,Magda Röhler

doi:10.1186/s13148-016-0270-x

Emily Eva Holmes, Jörn Dietrich + Show 9 more

Open Access

https://doi.org/10.1186/s13148-016-0270-x

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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.

Highlights

Molecular biomarkers that might help to distinguish between more aggressive and clinically insignificant prostate cancers (PCa) are still urgently needed
A histogram of Methylated pituitary homeobox 3 (PITX3) (mPITX3) showed a bell curve with a minor depression at ≈68 % (Fig. 3a). mPITX3 levels as a continuous variable were related to prognostic clinicopathological variables and were found to be significantly correlated with the International Society of Urological Pathologists (ISUP) Gleason grading group (ρ = 0.112; p = 0.012), pathologic tumor category (ρ = 0.123; p = 0.006), presurgical prostatespecific antigen (PSA) (ρ = 0.134; p = 0.003), and the androgen receptor (AR) activity score (ρ = 0.154; p = 0.005) as obtained from The Cancer Genome Atlas (TCGA) [27] in the training cohort
In order to analyze the suitability of mPITX3 for the stratification of patients at risk for biochemical recurrence (BCR), mPITX3 was dichotomized by an optimized cutoff which was identified by an iterative approach

Summary

Introduction

Molecular 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. PITX3 DNA methylation (mPITX3) and its potential role as a prognostic biomarker were investigated. In the last couple of decades, prostatespecific antigen (PSA) screening has increased the number of early detected PCa [2]. Clinicopathological parameters, i.e., PSA values, tumor size, number of positive biopsies, and Gleason grading groups, as suggested by the International Society of Urological Pathologists (ISUP), guide the decision-making process when determining whether a patient may benefit from radical prostatectomy or can instead be closely monitored.

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