DNA hypermethylation of PITX2 is a marker of poor prognosis in untreated lymph node-negative hormone receptor-positive breast cancer patients.
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.
Nimmrich
Inko
I
Department of Biomedical Research and Development and Technology Development, Epigenomics AG, Berlin, Germany.
Sieuwerts
Anieta M
AM
Meijer-van Gelder
Marion E
ME
Schwope
Ina
I
Bolt-de Vries
Joan
J
Harbeck
Nadia
N
Koenig
Thomas
T
Hartmann
Oliver
O
Kluth
Antje
A
Dietrich
Dimo
D
Magdolen
Viktor
V
Portengen
Henk
H
Look
Maxime P
MP
Klijn
Jan G M
JG
Lesche
Ralf
R
Schmitt
Manfred
M
Maier
Sabine
S
Foekens
John A
JA
Martens
John W M
JW
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
D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D011987:Receptors, Steroid; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2