THE ROLE OF DNMT1, DNMT3B AND EZH2 METHYLTRANSFERASE GENES IN ABERRANT DNA METHYLATION IN SPORADIC AND FAMILIAL COLORECTAL AND ENDOMETRIAL CANCER

JOENSUU EI.; W. M. ABDEL-RAHMAN; NIEMINEN T.; J. LOTSARI; PAVICIC W.; PELTOMÄKI P.

Congreso; HGM2013/21st ICG; 2013

Objectives:Methyltransferase genes serve as important transcriptional regulators in cells essential for normal development and cell functioning. Methyltransferases DNMT1 and DNMT3B methylate DNA on the gene promoter areas which usually blocks the transcription of the same genes. EZH2 histone methyltransferase methylates specific sites on Histone 3 leading to condensed chromatin conformation and is also associated with transcriptional silencing.We wanted to test whether altered expression of these methyltransferase genes is associated with aberrant DNA methylation (e.g. CpG island methylator phenotype, CIMP) in colorectal (CRC) and endometrial tumors (EC) compared to normal tissues and to find out if expression changes can be detected prior to malignant transformation.Methods: We studied sections from formalin-fixed paraffin-embedded (FFPE) tissue blocks in familial and sporadic colorectal and endometrial cancers and precursors by immunohistochemical staining (IHC) for DNMT1, DNMT3B and EZH2 protein expression. DNA methylation status of 24 tumor suppressor gene promoters and LINE-1 was determined by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).Results: We observed increase in the DNMT1, DNMT3B and EZH2 expression in tumor and hyperplastic samples compared to normal tissues. Elevated expression levels of these methyltransferase genes were also associated with abnormal DNA methylation or CIMP phenotype in specific study groups when divided by tissue type, family category andmicrosatellite instability status.Conclusion: Higher expression levels of the studied methyltransferase genes in tumors suggest their role in carcinogenesis. As observed already in hyperplastic tissues, elevated levels of DNMT1, DNMT3B and EZH2 could be used as early markers for detecting tumor precursors. The association of observed expression changes when compared to altered DNA methylation status raises interest in studying the subject further, including the association of expression levels to DNA imprinting changes in cancer.