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

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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. 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).

Methods: mPITX3 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.

Results: In 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.

Conclusions: PITX3 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.

No MeSH data available.


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Survival according to combined mPITX3 and mPITX2 status. Kaplan-Meier analysis of BCR-free survival in prostate cancer patients stratified according to PITX3 and PITX2 DNA methylation status. Training cohort (n = 498, a): After a homogenous dropout within the first months after prostatectomy in all three groups, patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 182). Patients with high methylation in PITX2 and PITX3 genes present with the highest rate of BCR events (n = 67). Intermediate numbers of BCR events are observed in patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 169). Validation cohort (n = 300, b): Patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 136). Patients with high methylation in PITX2 and PITX3 genes present with the earliest BCR events (n = 32). Patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 82) show the highest number of BCR events, however, more protracted than patients with high methylation in both PITX genes
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Fig4: Survival according to combined mPITX3 and mPITX2 status. Kaplan-Meier analysis of BCR-free survival in prostate cancer patients stratified according to PITX3 and PITX2 DNA methylation status. Training cohort (n = 498, a): After a homogenous dropout within the first months after prostatectomy in all three groups, patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 182). Patients with high methylation in PITX2 and PITX3 genes present with the highest rate of BCR events (n = 67). Intermediate numbers of BCR events are observed in patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 169). Validation cohort (n = 300, b): Patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 136). Patients with high methylation in PITX2 and PITX3 genes present with the earliest BCR events (n = 32). Patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 82) show the highest number of BCR events, however, more protracted than patients with high methylation in both PITX genes

Mentions: Since both parameters showed excellent prognostic performance, the combination of mPITX2 and mPITX3 was tested in the TCGA collective. Here, mPITX2low and mPITX3low cases showed significantly longer BRC-free survival compared to patients with mPITX2high and/or mPITX3high (LR = 12.70, p = 0.002; Fig. 4a).Fig. 4


PITX3 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients after radical prostatectomy
Survival according to combined mPITX3 and mPITX2 status. Kaplan-Meier analysis of BCR-free survival in prostate cancer patients stratified according to PITX3 and PITX2 DNA methylation status. Training cohort (n = 498, a): After a homogenous dropout within the first months after prostatectomy in all three groups, patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 182). Patients with high methylation in PITX2 and PITX3 genes present with the highest rate of BCR events (n = 67). Intermediate numbers of BCR events are observed in patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 169). Validation cohort (n = 300, b): Patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 136). Patients with high methylation in PITX2 and PITX3 genes present with the earliest BCR events (n = 32). Patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 82) show the highest number of BCR events, however, more protracted than patients with high methylation in both PITX genes
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Fig4: Survival according to combined mPITX3 and mPITX2 status. Kaplan-Meier analysis of BCR-free survival in prostate cancer patients stratified according to PITX3 and PITX2 DNA methylation status. Training cohort (n = 498, a): After a homogenous dropout within the first months after prostatectomy in all three groups, patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 182). Patients with high methylation in PITX2 and PITX3 genes present with the highest rate of BCR events (n = 67). Intermediate numbers of BCR events are observed in patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 169). Validation cohort (n = 300, b): Patients with low methylation values in PITX2 and PITX3 genes show the lowest number of BCR events (n = 136). Patients with high methylation in PITX2 and PITX3 genes present with the earliest BCR events (n = 32). Patients with low methylation in one PITX gene member and high methylation in the other PITX gene member (n = 82) show the highest number of BCR events, however, more protracted than patients with high methylation in both PITX genes
Mentions: Since both parameters showed excellent prognostic performance, the combination of mPITX2 and mPITX3 was tested in the TCGA collective. Here, mPITX2low and mPITX3low cases showed significantly longer BRC-free survival compared to patients with mPITX2high and/or mPITX3high (LR = 12.70, p = 0.002; Fig. 4a).Fig. 4

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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. 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).

Methods: mPITX3 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.

Results: In 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.

Conclusions: PITX3 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.

No MeSH data available.


Related in: MedlinePlus