DNA Methylation of the PITX2 Gene Promoter Region is a Strong Independent Prognostic Marker of Biochemical Recurrence in Patients With Prostate Cancer After Radical Prostatectomy

Weiß, Günter; Cottrell, Susan; Distler, Jürgen; Schatz, Philipp; Kristiansen, Glen; Ittmann, Michael; Haefliger, Carolina; Lesche, Ralf; Hartmann, Arndt; Corman, John M.; Wheeler, Thomas M.

doi:10.1016/j.juro.2008.11.120

Cited by 101 publications

(105 citation statements)

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“…This cohort is described in more detail elsewhere. 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.…”

Section: Cohorts and Patient Samplesmentioning

confidence: 99%

“…15 The previous study revealed that methylation at different levels could be found in most samples, and patient stratification into a high-risk and a low-risk group necessitated the use of a methylation cut-off. The cut-off had been defined with regard to an optimized clinical performance of the assay.…”

Section: Establishment and Verification Of A Methylation Cut-off For mentioning

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.…”

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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: Cohorts and Patient Samplesmentioning

confidence: 99%

Section: Establishment and Verification Of A Methylation Cut-off For 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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“…18,19 We next examined the relationship between biochemical recurrence and the HM or LM groups. Univariate analysis of those in the HM group vs LM group revealed significant differences in disease-free survival (Figure 1d, log-rank P-value ¼ 0.043).…”

Section: Biochemical Progression-free Survivalmentioning

confidence: 99%

DNA methylation of HOXD3 as a marker of prostate cancer progression

Kron

Liu

Pethe

et al. 2010

Laboratory Investigation

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DNA methylation in gene promoters causes gene silencing and is a common event in cancer development and progression. The ability of aberrant methylation events to serve as diagnostic and prognostic markers is being appreciated for many cancers, including prostate cancer. Using quantitative MethyLight technology, we evaluated the relationship between HOXD3 methylation and clinicopathological parameters including biochemical recurrence, pathological stage, Gleason score (GS), and Gleason pattern in a series of 232 radical prostatectomies performed between 1998 and 2001. HOXD3 methylation was significantly greater in GS 7 cancers vs GSr6 cancers (P-value o0.001) as well as pT3/pT4 vs pT2 cancers (P-value o0.001). The proportion of cases with high methylation in GS 7 vs rGS 6 and pT3/pT4 vs pT2 were also significantly different (P-values ¼ 0.002 and 0.005, respectively). There were also significant increases in methylation from Gleason pattern 2-3 and from pattern 3 to 4/5 (paired t-test P-values ¼ 0.01 and o0.001, respectively), whereas methylation from lymph node metastases was decreased when compared with matched tumor tissue (P-value ¼ 0.029). HOXD3 methylation was associated with biochemical recurrence in univariate analysis (P-value ¼ 0.043) and showed evidence for interaction with pathological stage as a predictor variable in Cox regression analysis (P-value ¼ 0.028). The results indicate that HOXD3 methylation distinguishes low-grade prostate cancers from intermediate and high-grade ones and may also have prognostic value when considered together with pathological stage.

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“…[7][8][9] In prostate cancer, hypermethylation of several genes has been associated with tumor aggressiveness in terms of clinical-pathological characteristics, biochemical recurrence, and/or mortality from prostate cancer. [10][11][12][13][14][15][16] Global hypomethylation, which may cause reactivation of the transcription of oncogenes and transposable elements and increases chromosomal instability and loss of imprinting, 17,18 has been less extensively investigated. We have recently conducted a systematic review of studies on prostatic tumor global hypomethylation and prostate cancer progression: 19 although studies were heterogeneous and mostly based on a limited sample size, global hypomethylation was reported to be associated with high Gleason score, advanced tumor stage, high pre-operative PSA, and presence of metastasis.…”

Section: Introductionmentioning

confidence: 99%

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

et al. 2016

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Aberrant DNA methylation seems to be associated with prostate cancer behavior. We investigated LINE-1 methylation in prostate cancer and non-neoplastic tissue adjacent to tumor (NTAT) in association with mortality from prostate cancer. We selected 157 prostate cancer patients with available NTAT from 2 cohorts of patients diagnosed between 1982-1988 and 1993-1996, followed up until 2010. An association between LINE-1 hypomethylation and prostate cancer mortality in tumor was suggested [hazard ratio per 5% decrease in LINE-1 methylation levels: 1.40, 95% confidence interval (CI): 0.95-2.01]. After stratification of the patients for Gleason score, the association was present only for those with a Gleason score of at least 8. Among these, low (<75%) vs. high (>80%) LINE-1 methylation was associated with a hazard ratio of 4.68 (95% CI: 1.03-21.34). LINE-1 methylation in the NTAT was not associated with prostate cancer mortality. Our results are consistent with the hypothesis that tumor tissue global hypomethylation may be a late event in prostate cancerogenesis and is associated with tumor progression.Abbreviations: NTAT, non-neoplastic tissue adjacent to tumor; LINE-1, long interspersed nuclear element-1; PIN, prostatic intraepithelial neoplasia; APC, adenomatous polyposis coli; GSTP1, glutathione S-transferase 1; TURP, transurethral resection of the prostate; HR, hazard ratio; CI, confidence interval; MAR, missing at random

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DNA Methylation of the PITX2 Gene Promoter Region is a Strong Independent Prognostic Marker of Biochemical Recurrence in Patients With Prostate Cancer After Radical Prostatectomy

Abstract: The prognostic information provided by PITX2 methylation adds significantly to currently used clinical variables such as Gleason grade and stage. Therefore, it could contribute to better counseling in patients with prostate cancer.

Cited by 101 publications

References 18 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

DNA methylation of HOXD3 as a marker of prostate cancer progression

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

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