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Lack of Telomerase RNA Gene hTERC Expression in Alternative Lengthening of Telomeres Cells Is Associated with Methylation of the hTERC Promoter¹

Cancer Research Campaign Department of Medical Oncology, University of Glasgow, Cancer Research Campaign Beatson Laboratories, Bearsden, Glasgow G61 1BD, United Kingdom [S. F. H., L. A. B., S. B., W. N. K.], Department of Gynaecology, University Hospital, 9700 RB, Groningen, the Netherlands [G. B. A. W., A. G. J. v. d. Z.], and Department of Pathology, G4 0SF, University of Glasgow, Scotland, United Kingdom [J. J. G.]

The immortal phenotype of most human cancers is attributable to telomerase expression. However, a number of immortal cell lines and tumors achieve telomere maintenance in the absence of telomerase via alternative mechanisms known as ALT (alternative lengthening of telomeres). Here we show that the promoter of the telomerase RNA gene (hTERC) is methylated in three of five ALT cell lines and is associated with a total absence of hTERC expression in the three lines. Treatment with 5-azacytidine in combination with trichostatin A resulted in partial demethylation of the hTERC promoter and expression of the gene. Partial methylation was detected in tumors (5%) and in immortal cell lines (27%). Cell lines with partial methylation express hTERC. Only in ALT cell lines does there appear to be a strong correlation between hTERC promoter hypermethylation and lack of hTERC expression.

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