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.

The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival

“…The ROC analysis demonstrated that necrosis had the highest AUC value for assessing the TERT promoter mutation status, and Pearson's chi‐squared test showed that necrosis was positively associated with the TERT promoter mutation status. Our study showed that TERT promoter mutations (66.42%) occur in many primary GBMs, and the frequency at which these were detected was in line with previous studies (58%‐75%) 21, 22. TERT promoter mutations are frequency associated with malignant tumor progression and a capacity for enhanced cell proliferation 23.…”

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

“…TERT promoter mutations are relatively frequent in human cancers characterized by low rates of self‐renewal, such as gliomas, bladder cancers, and melanoma,13, 14 and have been identified as recurrent somatic mutation in regulatory regions of human cancer genomes 15. The aims of this study were 2‐fold: (1) to determine whether TERT promoter mutations could be detected in plasma cfDNA in patients with HCC but also in patients with cirrhosis at risk for HCC; and (2) to characterize patients with HCC or cirrhosis with high frequency of TERT promoter mutations.…”

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

“…In our study, we identified TERT promoter mutations in small number of cases that exhibited different stages, invasiveness, and histologies, hindering meaningful statistical associations. The TERT mutation profile has been associated with other molecular features in several tumor types, in particular an interesting association with BRAF mutation in skin melanomas and thyroid cancer [3,4]. The frequency and clinical impact of BRAF mutations in TGCT is still controversial [25,26].…”

“…One of the key human cancer hallmarks is the abnormal upregulation of telomerase, that is codified by the telomerase reverse transcriptase (TERT) gene [1]. Recent studies identified the presence of hotspot somatic mutations in the promoter region of TERT gene, specifically the −124:C>T and −146:C>T mutations, in a range of human cancers such as bladder, gliomas, thyroid and melanoma [2][3][4][5]. These mutations have been shown to create a new binding motif sites for ETS transcription factors, which induces upregulation of TERT levels [2,5,6].…”