RASSF1A and CDH1 hypermethylation as potential epimarkers in breast cancer

Article type: Research Article

Authors: Sebova, Katarina^a | Zmetakova, Iveta^a | Bella, Vladimir^b | Kajo, Karol^c | Stankovicova, Iveta^d | Kajabova, Viera^a | Krivulcik, Tomas^a | Lasabova, Zora^e | Tomka, Miroslav^a | Galbavy, Stefan^{f; g; h} | Fridrichova, Ivana^{a; *}

Affiliations: [a] Laboratory of Cancer Genetics, Cancer Research Institute of the Slovak Academy of Sciences, Bratislava, Slovakia | [b] Department of Mammology, St. Elizabeth Cancer Institute, Bratislava, Slovakia | [c] Department of Pathology, Jessenius Faculty of Medicine, Comenius University and Faculty Hospital, Martin, Slovakia | [d] Department of Information Systems, Faculty of Management, Comenius University, Bratislava, Slovakia | [e] Department of Molecular Biology, Jessenius Faculty of Medicine, Comenius University and Faculty Hospital, Martin, Slovakia | [f] St. Elizabeth University College of Health and Social Work, Bratislava, Slovakia | [g] Department of Pathology, St. Elizabeth Cancer Institute, Bratislava, Slovakia | [h] Institute of Forensic Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia

Correspondence: [*] Corresponding author: Ivana Fridrichova, Ph.D., Laboratory of Cancer Genetics, Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava, Slovak Republic. Tel.: +421 2 59327 221; Fax: +421 2 59327 250; E-mail: [email protected].

Abstract: Breast cancer is the most common cancer in women worldwide, representing 28.2% of all female malignancies. In addition to genetic changes, epigenetic events, as aberrant DNA methylation and histone modification, are responsible for cancer development. Many tumour suppressor genes are inactivated by DNA hypermethylation, which could be utilized for identification of new epigenetic biomarkers. To investigate the relation between DNA methylation level and breast cancer progression, we analysed DNA methylation in RASSF1A and CDH1 promoters using quantitative multiplex methylation-specific PCR in paraffin-embedded tumour tissues and blood samples from 92 breast cancer patients and 50 controls, respectively. The associations between RASSF1A and CDH1 methylation levels and clinico-pathological parameters were tested by Kruskal-Wallis and van der Waerden ANOVA tests. Out of 92 breast cancer patients, 76 (82.6%) manifested various levels of RASSF1A (range from 1.20 to 92.63%) and 20 (21.7%) of CDH1 (range from 1.20 to 79.62%) methylation. However, no methylation was found in 50 controls. Increasing trends in RASSF1A methylation were observed in tumour size, lymph node status and TNM stage, but only CDH1 methylation levels showed statistically significant differences between the patient subgroups in lymph node status and IHC subtype. Overall, stable relatively high RASSF1A methylation could be utilised as universal tumour marker and the less frequent but highly methylated CDH1 promoter can serve for identification of potentially metastasising tumours.

Keywords: Breast cancer, DNA hypermethylation, quantitative assay, RASSF1A methylation, CDH1 methylation, epigenetic biomarkers

DOI: 10.3233/CBM-2012-0230

Journal: Cancer Biomarkers, vol. 10, no. 1, pp. 13-26, 2012