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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Patrick J. Killela
  • Zachary J. Reitman
  • Yuchen Jiao
  • Chetan Bettegowda
  • Nishant Agrawal
  • Luis A. Diaz Jr.
  • Allan H. Friedman
  • Henry Friedman
  • Gary L. Gallia
  • Beppino C. Giovanella
  • Arthur P. Grollman
  • Tong-Chuan He
  • Yiping He
  • Ralph H. Hruban
  • George I. Jallo
  • Alan K. Meeker
  • George J. Netto
  • B. Ahmed Rasheed
  • Gregory J. Riggins
  • Thomas A. Rosenquist
  • Mark Schiffman
  • Ie-Ming Shih
  • Dan Theodorescu
  • Michael S. Torbenson
  • Victor E. Velculescu
  • Tian-Li Wang
  • Nicolas Wentzensen
  • Laura D. Wood
  • Ming Zhang
  • Roger E. McLendon
  • Darell D. Bigner
  • Kenneth W. Kinzler
  • Bert Vogelstein
  • Nickolas Papadopoulos
  • Hai Yan
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)6021-6026
JournalProceedings of the National Academy of Sciences
Volume110
Issue number15
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes