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Methylation Profile Analysis of DNA Repair Genes in Hepatocellular Carcinoma With MS-MLPA

Ozer, Ozge MD; Bilezikci, Banu MD; Aktas, Sema MD; Sahin, Feride I. MD, PhD

doi: 10.1097/PDM.0b013e31828ed856
Original Articles

Hepatocellular carcinoma (HCC) is one of the rare tumors with well-defined risk factors. The multifactorial etiology of HCC can be explained by its complex molecular pathogenesis. In the current study, the methylation status of 7 genes involved in DNA repair mechanisms, namely MLH1, PMS2, MSH6, MSH2, MGMT, MSH3, and MLH3, was investigated in tumor samples from HCC patients, using the methylation-specific–multiplex ligated probe amplification method and the results were correlated with available clinical findings. The most common etiological factor in these cases was the presence of hepatitis B alone (47.2%). Among the 56 cases that were studied, promoter methylation was detected in at least one of the genes in 27 (48.2%) cases, only in 1 gene in 13 (23.2%) cases, and in >1 gene in 14 (25%) cases. Of the 7 genes investigated, methylation was most frequently observed in MSH3, in 14 (25%) cases. Methylation of at least 1 gene was significantly more frequent in patients with single tumors than multifocal tumors. There were significant differences regarding hepatitis B status, Child Class, tumor number, grade, and TNM stage in cases where PMS2 methylation was detected. Our results suggest that methylation of genes involved in mismatch repair may be responsible in the pathogenesis of HCC, and evaluating changes in multiple genes in these pathways simultaneously would be more informative. Despite being a robust and relatively inexpensive method, the methylation-specific–multiplex ligated probe amplification assay could be more extensively applied with improvements in the currently intricate data analysis component.

Department of Medical Genetics, Pathology, and General Surgery, Faculty of Medicine, Baskent University, Ankara, Turkey

Supported by Baskent University Scientific Research Committee (Project Number: KA09/185).

The authors declare no conflict of interest.

Reprints: Feride I. Sahin, MD, PhD, Department of Medical Genetics, Baskent University Faculty of Medicine, Kubilay sok. No: 36 Maltepe 06570, Ankara-Turkey (e-mail:

© 2013 by Lippincott Williams & Wilkins.