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Open Access Research article

Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome

Jia Xu16, Priya B Shetty25, Weiwei Feng17, Carol Chenault4, Robert C Bast1, Jean-Pierre J Issa38, Susan G Hilsenbeck24* and Yinhua Yu17*

Author Affiliations

1 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

2 Dan L Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

3 Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

4 Lester and Sue Smith Breast Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

5 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

6 Graduate School of Biomedical Science, The University of Texas, Houston, TX, 77030, USA

7 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

8 Fels Institute for Cancer and Molecular Biology, Temple University, 3307 North Broad Street, Philadelphia, PA, 19140, USA

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BMC Cancer 2012, 12:243  doi:10.1186/1471-2407-12-243

Published: 13 June 2012

Abstract

Background

Aberrant promoter CpG island hypermethylation is associated with transcriptional silencing. Tumor suppressor genes are the key targets of hypermethylation in breast cancer and therefore may lead to malignancy by deregulation of cell growth and division. Our previous pilot study with pairs of malignant and normal breast tissues identified correlated methylation of two pairs of genes - HIN-1/RASSFIA and RIL/CDH13 - with expression of estrogen receptors (ER), progesterone receptors (PR), and HER2 (HER2). To determine the impact of methylation on clinical outcome, we have conducted a larger study with breast cancers for which time to first recurrence and overall survival are known.

Methods

Tumors from 193 patients with early stage breast cancer who received no adjuvant systemic therapy were used to analyze methylation levels of RIL, HIN-1, RASSF1A and CDH13 genes for associations with known predictive and prognostic factors and for impact on time to first recurrence and overall survival.

Results

In this study, we found that ER was associated with RASSF1A methylation (p < 0.001) and HIN-1 methylation (p = 0.002). PR was associated with RIL methylation (p = 0.012), HIN-1 (p = 0.002), and RASSF1A methylation (p = 0.019). Tumor size was associated with RIL and CDH13 methylation (both p = 0.002), and S-phase was associated with RIL methylation (p = 0.036). Only RASSF1A was associated with worse time to first recurrence (p = 0.045) and worse overall survival (p = 0.016) after adjusting for age, tumor size, S-phase, estrogen receptor and progesterone receptor.

Conclusions

Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancers was associated with clinical characteristics, but only RASSF1A methylation was associated with time to first recurrence and overall survival. Our data suggest that RASSF1A methylation could be a potential prognostic biomarker.