PITX2的DNA高甲基化是未经治疗的淋巴结阴性激素受体阳性乳腺癌患者预后不良的一个标志物。

DNA hypermethylation of PITX2 is a marker of poor prognosis in untreated lymph node-negative hormone receptor-positive breast cancer patients.

作者信息

Nimmrich Inko, Sieuwerts Anieta M, Meijer-van Gelder Marion E, Schwope Ina, Bolt-de Vries Joan, Harbeck Nadia, Koenig Thomas, Hartmann Oliver, Kluth Antje, Dietrich Dimo, Magdolen Viktor, Portengen Henk, Look Maxime P, Klijn Jan G M, Lesche Ralf, Schmitt Manfred, Maier Sabine, Foekens John A, Martens John W M

机构信息

Department of Biomedical Research and Development and Technology Development, Epigenomics AG, Berlin, Germany.

出版信息

Breast Cancer Res Treat. 2008 Oct;111(3):429-37. doi: 10.1007/s10549-007-9800-8. Epub 2007 Oct 28.

DOI:10.1007/s10549-007-9800-8

PMID:17965955

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.

摘要

背景

在本研究中，我们评估了PITX2 DNA甲基化是否为淋巴结阴性（LNN）、类固醇激素受体阳性（HR +）乳腺癌患者疾病复发的标志物。此外，我们研究了PITX2 DNA甲基化与PITX2基因表达之间的关联。

患者与方法

对412例未接受任何辅助全身治疗的LNN/HR +乳腺癌患者的肿瘤组织进行PITX2 DNA甲基化检测。此外，对32个乳腺癌细胞系进行了PITX2 DNA甲基化和mRNA表达评估。

结果

在单变量Cox回归分析中，PITX2的DNA甲基化作为连续变量与早期远处转移（HR = 1.71；P < 0.01）和较差的总生存期（HR = 1.71；P < 0.01）相关。在多变量分析中，连同已确定的预后因素年龄、肿瘤大小、肿瘤分级以及类固醇激素受体水平，这两个关联均保持其显著性（无病生存期，HR = 1.74；P < 0.01；总生存期，HR = 1.46；P = 0.02）。在乳腺癌细胞系中，PITX2 DNA甲基化与PITX2A和PITX2B mRNA表达呈负相关（P < 0.01）。