gms | German Medical Science

Objective: Telomerase activation and expression are considered one of the key features in tumorigenesis. Currently, methylations and hotspot mutations of the promoter of the catalytic subunit of the Telomerase (hTERT, human Telomerase Reverse Transcriptase) are discussed as main potential underlying mechanisms. Since varying hTERT expression but lack of hotspot mutations have been reported in pituitary adenomas (PA), we thus aimed to investigate the role of promoter methylation in this context.

Method: DNA was isolated from formalin-fixed paraffin-embedded tumor samples of 85 primary and 15 recurrent PA diagnosed from 1996 to 2012. After bisulfite conversion, DNA from representative tumor material was subjected to methylation-specific PCR.

Results: 40 females (47%) and 45 males (53%) with a median age of 53 years were included. At initial diagnosis, tumor diameter was >1 cm in 75 and <1 cm in 10 cases. Immunhistochemical staining revealed positivity for Gonadotropin, Prolactin, Growth Hormon, ACTH and Thyreotropin in 24, 10, 10, 16 and 1 cases, respectively, while 10 plurihormonal and 14 non-secretory adenomas were included. hTERT promoter methylation was detected in 23 of 85 samples (27%). Methylation was more frequently in males than in females (40% vs. 13%, p=.007) but was independent of patients' age and tumor size. Among different PA subtypes, rates of methylation varied between 0 and 40% without reaching level of significance and did not correlate with endocrine activity measured by median serum hormone concentrations. Promoter methylation did not differ between primary diagnosed (27%) and recurrent adenomas (33%) and remained unchanged in individual clinical course. Median follow-up was 22 months and was available in 75 of 85 patients (88%). While death occurred in 2 non-methylated individuals a few days after surgery, recurrence was observed in 6 individuals with (37.5%) and 10 individuals without (62.5%) promoter methylation (p=n.s.). Median progression free survival (PFS) was 44 and 95 months in patients with and without promoter methylation, respectively, but did not correlate significantly with methylation status.

Conclusions: hTERT promoter methylation is detectable in nearly one third of PA, independent of adenoma subtype and is considerably more frequent in males than in females. Methylation is independent of endocrine activity, and remains unchanged during the clinical course and appears not to be associated with patients' prognosis.

Note: This research was funded by the Deutsche Gesellschaft für Neurochirurgie, „Stiftung neurochirugische Forschung“.