DNA-methylation of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients – Technical and clinical validation in a multi-centre setting in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) PathoBiology group

Maier, Sabine; Nimmrich, Inko; Koenig, Thomas; Eppenberger‐Castori, Serenella; Bohlmann, Inga; Paradiso, Angelo; Spyratos, Frédérique; Thomssen, Christoph; Mueller, Volkmar; Nährig, Jörg; Schittulli, F.; Kates, Ronald; Lesche, Ralf; Schwope, Ina; Kluth, Antje; Marx, Almuth; Martens, John W.M.; Foekens, John A.; Harbeck, Nadia

doi:10.1016/j.ejca.2007.04.025

Cited by 106 publications

(117 citation statements)

References 28 publications

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“…The ability of the microarray method to determine outcome was confirmed with a quantitative DNA methylation assay. 66 The relationship between PITX2 DNA methylation and outcome in lymph node-negative ER-positive breast cancer patients treated with adjuvant tamoxifen was subsequently validated in two independent multicentre studies. The first of these involved extracts of frozen tumours from 236 women treated at five different European centres, 66 while the second used paraffin-embedded tumour tissue from 399 patients treated at 10 European centres.…”

Section: Breast Cancermentioning

confidence: 99%

“…66 The relationship between PITX2 DNA methylation and outcome in lymph node-negative ER-positive breast cancer patients treated with adjuvant tamoxifen was subsequently validated in two independent multicentre studies. The first of these involved extracts of frozen tumours from 236 women treated at five different European centres, 66 while the second used paraffin-embedded tumour tissue from 399 patients treated at 10 European centres. 67 Based on the results from these two studies, PITX2 DNA methylation is a potential biomarker for predicting outcome in patients with newly diagnosed lymph node-negative steroid hormone receptorpositive breast cancer treated with tamoxifen monotherapy.…”

Section: Breast Cancermentioning

confidence: 99%

“…Using DNA methylation arrays, Maier et al 66 investigated the potential ability of 117 candidate genes to predict outcome in 109 lymph node-negative ER-positive breast cancers treated with adjuvant tamoxifen. Of the 117 genes investigated, methylation of the upstream promoter region of the PITX2 gene gave the strongest correlation with metastasis-free survival.…”

Section: Breast Cancermentioning

confidence: 99%

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Methylated genes as new cancer biomarkers

Duffy

Napieralski

Martens

et al. 2009

European Journal of Cancer

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Methylated genes as new cancer biomarkersBrünner, Nils; Duffy, M.J; Napieralski, R.; Martens, J.W.M. ; Span, P.N. ; Spyratos, F.; Sweep, F.C.G.J.; Foekens, J.A. ; Schmitt, M. GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2 for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene methylation need to be standardised, simplified and evaluated in external quality assurance programmes. It is concluded that methylated genes have the potential to provide a new generation of cancer biomarkers.

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Section: Breast Cancermentioning

confidence: 99%

Section: Breast Cancermentioning

confidence: 99%

Section: Breast Cancermentioning

confidence: 99%

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Methylated genes as new cancer biomarkers

Duffy

Napieralski

Martens

et al. 2009

European Journal of Cancer

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“…[22][23][24][25] In a subsequent study, PITX2 methylation was found to be strongly associated with biochemical recurrence in prostate cancer patients after radical prostatectomy. 26 In multivariate analysis, PITX2 methylation contributed significant independent prognostic information to established clinico-pathological factors (age, pT stage, Gleason score, pre-surgical prostate-specific antigen).…”

mentioning

confidence: 99%

Development of a Diagnostic Microarray Assay to Assess the Risk of Recurrence of Prostate Cancer Based on PITX2 DNA Methylation

Schatz

Dietrich

Koenig

et al. 2010

The Journal of Molecular Diagnostics

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Prostate cancer is among the most common cancers. Although it has a relatively good prognosis , 15 to 30% of men with prostate cancer experience a relapse after radical prostatectomy. Identifying patients with an aggressive tumor will therefore help to improve prostate cancer management. DNA methylation of PITX2 has been established in several studies as a prognostic biomarker for breast and prostate cancer. These case control studies were conducted using research assay components; to facilitate its use in a diagnostic setting, the PITX2 biomarker was transferred to a validated diagnostic platform, the Affymetrix GeneChip System. A customized microarray (Epichip PITX2) was designed using features in high redundancy to ensure a robust determination of the methylation state of the PITX2 promoter. The developed method allowed for accurate assessment of prognosis in prostate cancer patients who underwent radical prostatectomy. Determination of PITX2 methylation in formalin-fixed and paraffin-embedded tissue samples from a cohort of 157 prostatectomy patients resulted in an excellent level of concordance of the clinical classification, as well as the measured output between the research assay and the Epichip PITX2. These analytical performance results describe the Epichip PITX2 as a robust and reliable diagnostic tool for assessing the methylation status of PITX2, enabling an improved outcome prediction in cancer patients following radical prostatectomy. Prostate cancer affects one in six men and is the fifth most common cancer in the world. It is the second most common cancer in men, with about 900,000 new cases expected in 2010. 1Radical prostatectomy is commonly used as potentially curative treatment in patients with clinically localized prostate cancer. However, recurrent rise in prostate specific antigen affects 15 to 30% of men.2 Consequently, the stratification of individuals based on the likelihood of cancer recurrence in men at high risk for prostate cancer progression and men at low risk is very important. This classification influences patient decision-making and results in modified treatment plans.DNA methylation plays an important role in fundamental biological processes, such as development and cell differentiation (for review 3 ). In addition, DNA methylation has been shown to play a major role in carcinogenesis (for review 4 -6 ), suggesting that DNA methylation analysis may be a valuable source for cancer biomarkers.Identification of genes that undergo cancer-specific changes of CpG methylation and correlation of these data with tumor stage, progression, and long-term prognosis are becoming increasingly common. Several studies report the suitability of DNA methylation as a biomarker for prognosis in various cancers, ie, breast, prostate, gastric, colon, cervical, and ovarian cancers.7-21 DNA methylation of PITX2 has been shown to be strongly associated with a poor outcome in lymph-node negative, hormone-receptor positive breast cancer, as well as in lymph node-positive, estrogen receptor-positive ...

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“…The methylation of DNA dinucleotides in this gene is a common early event subsequent to the onset of cancer (58)(59)(60). Methylation patterns specific to tumor subtypes, including breast cancer, are reportedly associated with clinical outcomes (61)(62)(63). Several studies reported that PITX2 DNA methylation was associated with a high risk of relapse in lymph node metastasis-positive, hormone receptor-positive breast cancer patients undergoing whole body adjuvant tamoxifen therapy (64,65).…”

Section: Methylation Of Paired-like Homeodomain 2 (Pitx2p2)mentioning

confidence: 99%

Current status of the prognostic molecular biomarkers in breast cancer: A systematic review

et al. 2017

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Abstract. Biomarkers that facilitate the prediction of breast cancer prognosis can improve the quality of life in patients during the long period of illness and treatment. Particularly in recent years, with the advent of a more exhaustive analysis of genetic information and gene products, the molecular mechanisms at play during breast cancer have gradually become clearer. In the present study, a systematic review of the literature between 2009 and 2014 was conducted by searching for the keywords ʻbreast cancerʼ, ʻbiomarkersʼ, ʻdiagnosisʼ, ʻprognosisʼ and ʻdrug responseʼ to clarify the present state of knowledge regarding biomarkers. In the final analysis, 16 studies on biomarkers for the breast cancer prognosis were retrieved. From these, 7 biomarkers in 9 studies were found to be strongly reliable predictors of prognosis and a further 7 biomarkers in 7 studies were poorly reliable. The use of these prognostic biomarkers should increase the options available for treatment algorithms.

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Cited by 106 publications

References 28 publications

Methylated genes as new cancer biomarkers

Methylated genes as new cancer biomarkers

Development of a Diagnostic Microarray Assay to Assess the Risk of Recurrence of Prostate Cancer Based on PITX2 DNA Methylation

Current status of the prognostic molecular biomarkers in breast cancer: A systematic review

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