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

Killela, Patrick J. ; Reitman, Zachary J. ; Jiao, Yuchen ; Bettegowda, Chetan ; Agrawal, Nishant ; Diaz Jr., Luis A. ; Friedman, Allan H. ; Friedman, Henry ; Gallia, Gary L. and Giovanella, Beppino C. , et al. (2013) In Proceedings of the National Academy of Sciences 110(15). p.6021-6026
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
110
issue
15
pages
6021 - 6026
publisher
National Academy of Sciences
external identifiers
  • wos:000317537900058
  • scopus:84876067164
  • pmid:23530248
ISSN
1091-6490
DOI
10.1073/pnas.1303607110
language
English
LU publication?
yes
id
ffecfaf3-3211-4e32-9008-8198f625fe5e (old id 3851323)
date added to LUP
2016-04-01 09:54:13
date last changed
2022-04-27 08:13:08
@article{ffecfaf3-3211-4e32-9008-8198f625fe5e,
  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 (&gt;= 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.}},
  author       = {{Killela, Patrick J. and Reitman, Zachary J. and Jiao, Yuchen and Bettegowda, Chetan and Agrawal, Nishant and Diaz Jr., Luis A. and Friedman, Allan H. and Friedman, Henry and Gallia, Gary L. and Giovanella, Beppino C. and Grollman, Arthur P. and He, Tong-Chuan and He, Yiping and Hruban, Ralph H. and Jallo, George I. and Mandahl, Nils and Meeker, Alan K. and Mertens, Fredrik and Netto, George J. and Rasheed, B. Ahmed and Riggins, Gregory J. and Rosenquist, Thomas A. and Schiffman, Mark and Shih, Ie-Ming and Theodorescu, Dan and Torbenson, Michael S. and Velculescu, Victor E. and Wang, Tian-Li and Wentzensen, Nicolas and Wood, Laura D. and Zhang, Ming and McLendon, Roger E. and Bigner, Darell D. and Kinzler, Kenneth W. and Vogelstein, Bert and Papadopoulos, Nickolas and Yan, Hai}},
  issn         = {{1091-6490}},
  language     = {{eng}},
  number       = {{15}},
  pages        = {{6021--6026}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences}},
  title        = {{TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal}},
  url          = {{http://dx.doi.org/10.1073/pnas.1303607110}},
  doi          = {{10.1073/pnas.1303607110}},
  volume       = {{110}},
  year         = {{2013}},
}