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Open Access Research article

Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers

Weiwei Feng1, Rosaria Orlandi2, Naiqing Zhao3, Maria Luisa Carcangiu2, Elda Tagliabue2, Jia Xu4, Robert C Bast4 and Yinhua Yu14*

Author Affiliations

1 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China

2 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

3 Department of Bioinfomatics, Shanghai Medical College, Fudan University, Shanghai, China

4 Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA

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BMC Cancer 2010, 10:378  doi:10.1186/1471-2407-10-378

Published: 20 July 2010

Abstract

Introduction

Metastasis represents a major adverse step in the progression of breast carcinoma. Lymph node invasion is the most relevant prognostic factor; however little is known on the molecular events associated with lymph node metastasis process. This study is to investigate the status and role of methylation in lymph node metastatic tumors.

Materials and methods

Bisulfite pyrosequencing is used to screen 6 putative tumor suppressor genes (HIN-1, RASSF1A, RIL, CDH13, RARβ2 and E-cadherin) in 38 pairs of primary breast tumors and lymph node metastases.

Results

We found that HIN-1, CDH13, RIL, RASSF1A and RARβ2 were frequently methylated both in primary and metastatic tissues (range: 55.3%~89.5%). E-cadherin was not frequently methylated in either setting (range: 18.4%~23.7%). The methylation status of HIN-1, CDH13, RIL, and RARβ2 in lymph nodes metastasis were correlated with that in primary tumors. The Pearson correlation values ranged from 0.624 to 0.472 (p values < 0.01 to 0.001). Interestingly, we observed an association between HIN-1 methylation and hormone status in metastatic lymph nodes. Hypermethylation of HIN-1 in metastasis lymph nodes was significantly associated with expression of ER (odds ratio, 1.070; P = 0.024) and with PR (odds ratio, 1.046; P = 0.026).

Conclusions

This study suggests that hypermethylation of tumor suppressor genes is extended from primary to metastatic tumors during tumor progression.