title: DNA hypermethylation of PITX2 is a marker of poor prognosis in untreated lymph node-negative hormone receptor-positive breast cancer patients.
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.
  
  
  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.
authors.affiliation: Department of Biomedical Research and Development and Technology Development, Epigenomics AG, Berlin, Germany.
authors.forename: Inko
authors.initials: I
authors.lastname: Nimmrich
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-van Gelder
authors.forename: Ina
authors.initials: I
authors.lastname: Schwope
authors.forename: Joan
authors.initials: J
authors.lastname: Bolt-de Vries
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Thomas
authors.initials: T
authors.lastname: Koenig
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartmann
authors.forename: Antje
authors.initials: A
authors.lastname: Kluth
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.forename: Viktor
authors.initials: V
authors.lastname: Magdolen
authors.forename: Henk
authors.initials: H
authors.lastname: Portengen
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Sabine
authors.initials: S
authors.lastname: Maier
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D011987:Receptors, Steroid / Q000032:analysis; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D011987:Receptors, Steroid; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2