DNA hypermethylation of PITX2 is a marker of poor prognosis in untreated lymph node-negative hormone receptor-positive breast cancer patients |
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Authors: | Inko Nimmrich Anieta M Sieuwerts Marion E Meijer-van Gelder Ina Schwope Joan Bolt-de Vries Nadia Harbeck Thomas Koenig Oliver Hartmann Antje Kluth Dimo Dietrich Viktor Magdolen Henk Portengen Maxime P Look Jan G M Klijn Ralf Lesche Manfred Schmitt Sabine Maier John A Foekens John W M Martens |
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Institution: | (1) Department of Biomedical Research and Development and Technology Development, Epigenomics AG, Berlin, Germany;(2) Department of Medical Oncology, Erasmus MC, Josephine Nefkens Institute, Room Be 400, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands;(3) Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany |
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Abstract: | Background In this study, we evaluated if PITX2 DNA methylation is a marker for disease recurrence in lymph node-negative (LNN), steroid hormone receptor-positive (HR+)
breast cancer patients. In addition, we studied the association between PITX2 DNA methylation and PITX2 gene expression. Patients and methods
PITX2 DNA-methylation was measured in tumor tissue from 412 LNN/HR+ breast cancer patients who had not received any adjuvant systemic
treatment. In addition, PITX2 DNA-methylation and mRNA expression was evaluated in 32 breast cancer cell lines. Results In univariate Cox regression analysis, DNA-methylation of PITX2 as a continuous variable was associated with early distant metastasis (HR = 1.71; P < 0.01) and poor overall survival (HR = 1.71; P < 0.01). In multivariate analysis together with the established prognostic factors age, tumor size and tumor grade, and steroid
hormone receptor levels, both associations retained their significance (for MFS, HR = 1.74; P < 0.01; for OS, HR = 1.46; P = 0.02). In the breast cancer cell lines, PITX2 DNA methylation was inversely association with PITX2A and PITX2B mRNA expression (P < 0.01). Conclusions Hypermethylation of PITX2 is, in cell lines, negatively associated with PITX2 mRNA expression and, in clinical specimens, positively associated with
breast cancer disease progression. |
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Keywords: | Breast cancer DNA-methylation Estrogen receptor PITX2 Prognosis |
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