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

作者：Patrick J. Killela, Zachary J. Reitman, Yuchen Jiao, Chetan Bettegowda, Nishant Agrawal, Luis Alberto Diaz, Allan H. Friedman, Henry S. Friedman, Gary L. Gallia, Beppino C. Giovanella, Arthur P. Grollman, Tong‐Chuan He, Yiping He, Ralph H. Hruban, George I. Jallo, Nils Mandahl, Alan Keith Meeker, Fredrik Mertens, George Jabboure Netto, B. Ahmed Rasheed, Gregory Joseph Riggins, Thomas A. Rosenquist, MARK H. SCHIFFMAN, Ie‐Ming Shih, Dan Theodorescu, Michael S Torbenson, Victor E. Velculescu, Tian‐Li Wang, Nicolas Wentzensen, Laura DeLong Wood, Ming Zhang, Roger E. McLendon, Darell D. Bigner, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Hai Yan · 发表于：Proceedings of the National Academy of Sciences · 年份：2013 · DOI：10.1073/pnas.1303607110 · 被引用次数：1399 · 研究领域：Telomeres, Telomerase, and Senescence、Cancer Research and Treatments、Renal and related cancers

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 ...