Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 15, Pages 6021-6026Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303607110
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Funding
- American Cancer Society Research Scholar Award [RSG-10-126-01-CCE]
- National Cancer Institute Grant [5R01-CA140316]
- Pediatric Brain Tumor Foundation Institute grant
- Voices Against Brain Cancer Foundation grant
- James S. McDonnell Foundation grant
- V Foundation
- Accelerate Brain Cancer Cure Foundation grant
- Burroughs Wellcome Career Award for Medical Scientists
- Johns Hopkins Clinician Scientist Award
- BSi Brain Science Translational Research grant
- Malia's Cord Foundation Grant
- Zickler Family Foundation
- Swim Across America
- Swedish Childhood Cancer Foundation
- Flight Attendant Medical Research Institute (FAMRI)
- FAMRI Clinical Innovator Award
- Lustgarten Foundation
- Sol Goldman Pancreatic Cancer Research Center
- Virginia and D. K. Ludwig Fund for Cancer Research
- National Institutes of Health Grant: Intramural Research Program of the National Cancer Institute
- National Institutes of Health Grant: National Institute of Neurological Disorders and Stroke Grant [5P50 NS20023]
- National Institutes of Health Grant: National Cancer Institute Specialized Program of Research Excellence [5P50 CA108785, CA121113, CA075115, CA104106, CA057345, CA129825, CA43460, CA57345, CA62924, P50DE019032, ES04068, CA172380]
- National Institutes of Health Grant: National Cancer Institute Contract [N01-CN-43309]
- National Institutes of Health Grant: National Cancer Institute Merit Award [R37 011898]
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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.
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