Open Access Highly Accessed Research article

Methylation signature of lymph node metastases in breast cancer patients

Zeinab Barekati1, Ramin Radpour1, Qing Lu2, Johannes Bitzer3, Hong Zheng45, Paolo Toniolo6, Per Lenner7 and Xiao Yan Zhong1*

Author Affiliations

1 Laboratory for Gynecological Oncology, Women’s Hospital/Department of Biomedicine, University of Basel, Hebelstrasse 20, CH 4031, Basel, Switzerland

2 Department of Breast Surgery, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China

3 Department of Obstetrics and Gynecology, Women’s Hospital, University of Basel, Schanzenstrasse 46, CH-4031, Basel, Switzerland

4 Department of Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China

5 Laboratory of Molecular Diagnosis of Cancer, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China

6 Department of Obstetrics & Gynecology, New York University School of Medicine / Institute Universitaire de Médecine Sociale et Preventive, CHUV, Rue du Bugnon 17, 1005, Lausanne, Switzerland

7 Department of Oncology, Umeå University Hospital, Campus Area, S-90185, Umeå, Sweden

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BMC Cancer 2012, 12:244  doi:10.1186/1471-2407-12-244

Published: 13 June 2012

Abstract

Background

Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers.

Methods

The quantitative methylation analysis was performed using the SEQUENOM’s EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).

Results

The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis.

Conclusions

The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.

Keywords:
Methylation; Metastasis; Breast cancer; Biomarker