gms | German Medical Science

Objective: Frequent activating mutations in the promoter region of the hTERT gene have recently been described in a number of cancers including malignant gliomas. The hTERT gene encodes the catalytic subunit of the telomerase gene. For the present study we have studied the incidence of hTERT mutations and their potential impact on patient survival in a large cohort of GBM.

Method: Tumor tissues from 192 patients with GBM were tested for hTERT promoter mutations by PCR and Sanger sequencing. For comparison, we also analyzed cases with anaplastic astrocytomas WHO grade III (n=9), or mixed gliomas WHO grade II (n=1) or grade III (n=1). Patients and tumors were also genotyped for a functional polymorphism of the hTERT promoter (rs2853669). MGMT promoter methylation status was assessed by pyrosequencing in 181 (89.2%) of cases. Relevant clinical data (age, KPI, extent of resection, adjuvant therapy, PFS, OS) were obtained from a prospectively maintained electronic database.

Results: We detected hTERT mutations in 143/178 (80.3%) of primary (pGBM), but in only 4/14 (28.6%) secondary glioblastomas (secGBM), and 3/11 (27.2%) of gliomas WHO grades II/III (p<0.001). The presence of a hTERT mutation proved to be a significant (negative) predictor of pGBM patient survival in univariate as well as multivariate analyses. hTERT mutations were not prognostic in patients, who had complete resections or temozolomide chemotherapy. Interestingly, the prognostic impact of the hTERT mutational status was also more or less restricted to cases with the rs2853669AA genotype.

Conclusions: These data provide further support for the concept of pGBM as a separate tumor entity. Importantly, the hTERT mutational status proved to be an independent predictor of patient survival. hTERT mutations had no prognostic impact in patients with complete resections and temozolomide chemotherapy, i.e. hTERT mutations seem to characterize tumors that benefit from aggressive treatment.