Multicenter Clinical Validation of
            <i>PITX2</i>
            Methylation as a Prostate Specific Antigen Recurrence Predictor in Patients With Post-Radical Prostatectomy Prostate Cancer

Bañez, Lionel L.; Sun, Leon; Leenders, Geert J.L.H. van; Wheeler, Thomas M.; Bangma, Chris H.; Freedland, Stephen J.; Ittmann, Michael; Lark, Amy L.; Madden, John F.; Hartman, Arndt; Weiß, Günter; Castaños‐Vélez, Esmeralda

doi:10.1016/j.juro.2010.03.012

Cited by 75 publications

(70 citation statements)

References 26 publications

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“…The clinical performance of the assay was then successfully validated using leftover DNA samples from the cohort, which were previously used to validate the microarray-based EpiChip PITX2. 17 The developed realtime PCR assay might be successfully applied to biopsy specimens in the future and therefore support the decisionmaking process when determining whether a prostate cancer patient will benefit from a radical prostatectomy or should be left untreated.…”

Section: E17mentioning

confidence: 99%

“…16,17 For cut-off establishment and verification, leftover bisulfite samples from 157 patient samples were taken from a previous study in which the cut-off was already transferred to the microarray-based EpiChip PITX2 microarray assay. 16 This cohort was obtained from the Virginia Mason Medical Center (Seattle, WA) and included patient samples from patients who were treated between 1996 and 2000 and were analyzed according to the protocol approved by the institutional review board.…”

Section: Cohorts and Patient Samplesmentioning

confidence: 99%

“…15,16 For the validation of the prognostic power of the developed assay, leftover bisulfite-converted DNA from the EpiChip PITX2 validation study was used. 17 During that previous study, cohorts were recruited retrospectively from four sites under institutional review board approval. Samples were obtained from patients who underwent radical prostatectomy between 1995 and 2001 at Baylor College of Medicine, Duke University, Durham Veterans Affairs Medical Center, and Erasmus Medical Center.…”

Section: Cohorts and Patient Samplesmentioning

confidence: 99%

“…In particular, PITX2 methylation was able to provide independent information on the risk of BCR in patients at intermediate risk (Gleason score of 7), which represents a high portion of all individuals with prostate cancer treated with radical prostatectomy and for whom the assessment of disease prognosis is particularly challenging. 15,17 PITX2 is a member of the homeobox gene family, which has been characterized extensively as a transcriptional factor involved in pattern formation in both invertebrate and vertebrate species. The protein encoded by PITX2 is involved in the development of several organs, including the heart, lungs, pituitary gland, and teeth, 18 and in the determination of left-right asymmetry during development.…”

mentioning

confidence: 99%

“…16 This microarray-based test (EpiChip PITX2; Epigenomics AG, Berlin, Germany) was developed for use with a validated diagnostic platform, the Affymetrix GeneChip System (Affymetrix, Santa Clara, CA). The clinical performance of the test was further successfully validated in a large retrospective cohort study 17 of >500 patients. However, the Affymetrix GeneChip System is nonstandard laboratory equipment, which limits the utility of this test.…”

mentioning

confidence: 99%

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Development and Clinical Validation of a Real-Time PCR Assay for PITX2 DNA Methylation to Predict Prostate-Specific Antigen Recurrence in Prostate Cancer Patients Following Radical Prostatectomy

Dietrich

Hasinger

Bañez

et al. 2013

The Journal of Molecular Diagnostics

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Prostate cancer is the most common cancer among men. The prospective discrimination of aggressive and clinically insignificant tumors still poses a significant and, as yet, unsolved problem. PITX2 DNA methylation is a strong prognostic biomarker in prostate cancer. Recently, a diagnostic microarray for prostate cancer prognosis based on PITX2 methylation has been developed and validated. Because this microarray requires nonstandard laboratory equipment, its use in a diagnostic setting is limited. This study aimed to develop and validate an alternative quantitative real-time PCR assay for measuring PITX2 methylation that can easily be established in clinical laboratories, thereby facilitating the implementation of this biomarker in clinical practice. A methylation cut-off for patient stratification was established in a training cohort (n Z 157) and validated in an independent test set (n Z 523) of men treated with radical prostatectomy. In univariate Cox proportional hazards analysis, PITX2 hypermethylation was a significant predictor for biochemical recurrence (P < 0.001, hazard ratio Z 2.614). Moreover, PITX2 hypermethylation added significant prognostic information (P Z 0.003, hazard ratio Z 1.814) to the Gleason score, pathological T stage, prostate-specific antigen, and surgical margins in a multivariate analysis. The clinical performance was particularly high in patients at intermediate risk (Gleason score of 7) and in samples containing high tumor cell content. This assay might aid in risk stratification and support the decision-making process when determining whether a patient might benefit from adjuvant treatment after radical prostatectomy. (J Mol Diagn 2013, 15: 270e279; http://dx.doi.org/10.1016/j.jmoldx.2012 In the western world, prostate cancer is by far the most common cancer and also one of the leading causes of cancer-related deaths among men.1 However, because of the relatively good prognosis of prostate cancer, only a relatively low percentage of men diagnosed as having localized prostate cancer will die of it. Prostate-specific antigen (PSA) screening for prostate cancer allows for early detection of prostate cancer and, regardless of the limitations of PSA and the problem of overdiagnosis, saves lives.

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Section: E17mentioning

confidence: 99%

Section: Cohorts and Patient Samplesmentioning

confidence: 99%

Section: Cohorts and Patient Samplesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Development and Clinical Validation of a Real-Time PCR Assay for PITX2 DNA Methylation to Predict Prostate-Specific Antigen Recurrence in Prostate Cancer Patients Following Radical Prostatectomy

Dietrich

Hasinger

Bañez

et al. 2013

The Journal of Molecular Diagnostics

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Environment, Epigenetics, and Diseases

Cheng¹,

Tang²

2012

Toxicology and Epigenetics

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The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer

Kloth¹,

Goering²,

Ribarska³

et al. 2012

Intl Journal of Cancer

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Epigenetic aberrations are frequent in prostate cancer and could be useful for detection and prognostication. However, the underlying mechanisms and the sequence of these changes remain to be fully elucidated. The tumor suppressor gene RARRES1 (TIG1) is frequently hypermethylated in several cancers. Having noted changes in the expression of its paralogous neighbor gene LXN at 3q25.32, we used pyrosequencing to quantify DNA methylation at both genes and determine its relationship with clinicopathological parameters in 86 prostate cancer tissues from radical prostatectomies. Methylation at LXN and RARRES1 was highly correlated. Increasing methylation was associated with worse clinical features, including biochemical recurrence, and decreased expression of both genes. However, expression of three neighboring genes was unaffected. Intriguingly, RARRES1 methylation was influenced by the genotype of the rs6441224 single-nucleotide polymorphism (SNP) in its promoter. We found that this SNP is located within an ETS-family-response element and that the more strongly methylated allele confers lower activity in reporter assays. Concomitant methylation of RARRES1 and LXN in cancerous tissues was also detected in prostate cancer cell lines and was shown to be associated with repressive histone modifications and transcriptional downregulation. In conclusion, we found that genotype-associated hypermethylation of the ETS-family target gene RARRES1 influences methylation at its neighbor gene LXN and could be useful as a prognostic biomarker.Prostate cancer (PCa) is the most common cancer among elderly men and has a relatively long natural history. Its highly variable course fuels a debate about optimal patient management and could reflect its pathogenetic and epigenetic heterogeneity.

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Multicenter Clinical Validation of PITX2 Methylation as a Prostate Specific Antigen Recurrence Predictor in Patients With Post-Radical Prostatectomy Prostate Cancer

Cited by 75 publications

References 26 publications

Development and Clinical Validation of a Real-Time PCR Assay for PITX2 DNA Methylation to Predict Prostate-Specific Antigen Recurrence in Prostate Cancer Patients Following Radical Prostatectomy

Development and Clinical Validation of a Real-Time PCR Assay for PITX2 DNA Methylation to Predict Prostate-Specific Antigen Recurrence in Prostate Cancer Patients Following Radical Prostatectomy

Environment, Epigenetics, and Diseases

The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer

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