High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression

Abstract

Meningiomas are common central nervous system tumors. The World Health Organization (WHO) defines three grades, predictive of the risk of recurrence. These tumors can relapse frequently and sometimes undergo malignant transformation. Maintenance of telomere length is a key process in malignant progression, and mutations in TERT promoter have recently been identified in various types of cancer. We sequenced the TERT promoter in 85 meningiomas from 73 patients. We found a high incidence of TERT promoter mutations in patients with meningiomas undergoing malignant histological progression (28%, n = 5/18 patients). In this subset of patients with histological progression, TERT promoter mutations were found in both the lowest and the highest grade tumors, and in both NF2-mutated and nonmutated samples. In contrast, one mutation was identified in 35 meningiomas without recurrence or progression, belonging to various histological grades. This sample was an aggressive meningioma in a patient who died shortly after surgery. Interestingly, tumors showing relapse without histological progression were not mutated for TERT promoter (n = 20). Finally, TERT promoter mutations were associated with a marked increase in TERT expression. Thus, TERT promoter mutations are pivotal genetic alterations involved in malignant progression of meningiomas and could be used as a biomarker to identify meningiomas at risk of malignant transformation.

Keywords: TERT promoter; malignant progression; meningioma; neurofibromatosis type 2.

Figure 1

TERT  expression is increased in  TERT ‐mutated meningioma samples. TERT‐mutated samples (red triangles) showed higher mean level of TERT expression than nonmutated samples (black dots) (Mann–Whitney P = 0.0001). Error bars represent SEM.

Figure 2

TERT  expression is increased in high‐grade meningioma samples. Mean level of expression of tumor samples in grade I, II and III meningiomas. (Kruskal–Wallis P = 0.008, Dunn's multiples comparison test). Error bars represent SEM. Red triangles stand for TERT‐mutated samples, and black dots for nonmutated samples.

Figure 3

Higher  TERT  expression in meningioma samples undergoing histological progression compared with single surgery samples and recurrent meningiomas without histological progression ( K ruskal–W allis P = 0.008). TERT promoter mutations (red triangles) are mostly identified in progressing samples. Of note, the only TERT‐mutated sample in the single surgery group is a grade II meningioma in a patient (#252) that died shortly after surgery of an extensive meningioma. Error bars represent SEM.