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

TLDR

Telomere maintenance in cancer relies on either alternative lengthening of telomeres driven by ATRX/DAXX mutations or telomerase activation via TERT promoter mutations, a mechanism recently uncovered in several tumor types. The study aimed to delineate which tumor types employ TERT promoter–driven telomerase activation. Researchers surveyed 1,230 tumors spanning 60 histologic categories to assess TERT promoter mutation frequencies. They found tumors segregated into low (<15%) and high (≥15%) mutation groups, with high‑frequency types—such as melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, tongue squamous cell carcinomas, medulloblastomas, and most primary glioblastomas—originating from tissues with low self‑renewal rates; TERT and ATRX mutations were mutually exclusive, and TERT mutations may serve as biomarkers for early detection and prognostication of certain cancers.

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 (&lt;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.