TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal

Abstract

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Fig. 1.

Frequency of TERT promoter mutations; 15 or more tumors were analyzed in 26 tumor types. Gliomas are divided into primary GBM, astrocytoma (including astrocytoma grades II and III, as well as secondary GBM), and oligodendroglioma.

Fig. 2.

Mutations of selected genes in glioma subtypes. (A) Distribution of TERT mutations and other genetic events in 51 primary GBMs. (B) Distribution of TERT mutations and other genetic events among 40 astrocytomas, including grades II–III astrocytomas and grade IV secondary GBMs. (C) Distribution of TERT mutations and other genetic events among 45 oligodendrogliomas. (D) Distribution of TERT mutations and other genetic events among 24 oligoastrocytomas. World Health Organization tumor grade is indicated under each column. Light gray cells denote WT status in tumors.