hTERT promoter methylation in meningiomas and central nervous hemangiopericytomas

Abstract

In meningiomas, prognostic impact of mutations in the human telomerase reverse transcriptase (hTERT) promoter region was recently shown, while studies of promoter methylation and analyses of hemangiopericytomas are lacking. hTERT promoter methylation was analyzed in 78 meningioma and 38 meningeal hemangiopericytoma samples by methylation-specific polymerase chain reaction (MS-PCR) and compared with histopathological and clinical variables and with immunohistochemical hTERT expression. Promoter methylation was found in 62 samples (53 %) and tended to be higher in meningiomas (N = 19/41, 46 %) than in hemangiopericytomas (N = 8/33, 24 %, p = .057). In meningiomas, methylation was 16, 60 and 77 % in grade I, II and III tumors (p < .001) and higher in recurrent (N = 33/37, 89 %) than in primary diagnosed (N = 19/41, 46 %) tumors (OR 5.14, 95 % CI 1.34-19.71, p = .017). Univariate analyses showed shorter mean progression free and overall survival in methylated than in unmethylated individuals (26 vs. 100 months; p = .045 and 110 vs. 113 months; p = .025, respectively). Moreover, hTERT expression was found in 70 % (N = 53) and was more frequent in methylated than in unmethylated samples (78 vs. 52 %, OR 3.36, 95 % CI 1.20-9.40, p = .021). In hemangiopericytomas, methylation was similar in grade II (24 %) and III (25 %, p > .05) and in primary (24 %) and recurrent tumors (40 %, p > .05). hTERT expression was similar as compared to meningiomas (74 %, N = 28, p > .05) but was independent of promoter methylation (OR 4.26, 95 % CI 0.47-39.0, p = .199). In meningeal tumors, hTERT promoter methylation is more common than mutations and in meningiomas but not in hemangiopericytomas positively correlated with WHO grade and hTERT expression.

TERTpromoter mutations are associated with poor prognosis and cell immortalization in meningioma

“…4,12,40,41 Corresponding data have been reported 1592 Spiegl-Kreinecker et al TERT promoter alterations of meningiomas for meningiomas, where TERT promoter methylation was associated with increasing tumor grade and upregulation of TERT mRNA expression. 13 In the latter study, a minor but significant impact of TERT promoter methylation on patient OS was detected in univariate analysis, which, however, lost significance in the multivariate setting. In our study, we have analyzed TERT promoter methylation in all TERTp-mut meningioma compared with a selection of TERTp-wt tumors positive and negative for telomerase reactivation.…”

“…This clearly indicates that TERT promoter mutation rather than methylation dominates telomerase activation in anaplastic meningiomas. In contrast, Furtjes et al 13 suggested enhanced TERT protein expression in methylated cases based on immunohistochemistry. This could be due to the different methods used for detection of TERT promoter methylation (methylation-specific PCR versus pyrosequencing) and gene expression (RT-PCR and telomeric repeat amplification protocol [TRAP] assay versus immunohistochemistry).…”

“…Hypermethylation was associated with enhanced TERT mRNA expression for example, in pediatric brain tumors 12 but also meningiomas. 13 A few studies on meningiomas have analyzed the presence of TERT promoter mutations so far, indicating that these noncoding genetic alterations in a small patient subgroup might be associated with enhanced risk for recurrence and progression. 4,[14][15][16] Consequently, in the present study we have comprehensively analyzed the impact of the TERT promoter mutation compared with methylation status on telomerase activity, TERT mRNA expression, telomere lengths, and cancer cell immortalization as well as clinical outcome.…”

Relationship between tumor location, size, and WHO grade in meningioma

“…9 Multiple independent groups have shown that TERT promoter mutations are associated with shorter time to recurrence, survival, and overall poor prognosis. 2,12,13,25 In addition to somatic mutations, specific DNA methylation patterns have recently been discovered that complement known chromosomal rearrangements that are associated with tumor grade and survival. 4,26 In contrast to mechanisms occurring within the meningioma, another possibility is that the immune environment and tumor-immune system interaction may alter tumor growth and drive the development of large size.…”

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

“…THOR was further explored in prostate cancer and has shown its role as a potential marker with diagnostic and prognostic properties [ 139 ]. These findings have been expanded upon by multiple groups implicating h TERT promoter methylation in h TERT upregulation, and further demonstrating not only its diagnostic but, importantly, its clinical significance in cancer prognostic including thyroid cancer, acute myeloid leukemia/myelodisplastic syndrome, esophageal carcinoma, meningioma, pituitary adenomas, colorectal cancer and hepatocellular carcinoma) [ 72 , 82 , 139 , 152 – 157 ]. In these studies, h TERT promoter hypermethylation was positively correlated with high h TERT expression, telomerase reactivation and in the vast majority of the cases correlated with worse clinical outcomes.…”