Patrick Killela1, Zachary J. Reitman1, Yuchen Jiao2, Chetan Bettegowda3,4, Nishant Agrawal5,4, Luis A. Díaz4, Allan H. Friedman1, Henry S. Friedman1, Gary L. Gallia3,5, Beppino C. Giovanella6, Arthur P. Grollman7, Tong‐Chuan He8, Yiping He1, Ralph H. Hruban9,10, George I. Jallo3, Nils Mandahl11, Alan K. Meeker9,12, Fredrik Mertens11, George J. Netto9,13,10, B. Ahmed Rasheed1, Gregory J. Riggins3, Thomas A. Rosenquist7, Mark Schiffman14, Ie-Ming Shih9,10, Dan Theodorescu15, Michael Torbenson9,10, Victor E. Velculescu4, Tian‐Li Wang9,10, Nicolas Wentzensen14, Laura D. Wood9,10, Ming Zhang4, Roger E. McLendon1, Darell D. Bigner1, Kenneth W. Kinzler4, Bert Vogelstein4, Nickolas Papadopoulos4, Hai Yan1
1The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, NC 27710;
2Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231;
3Departments of cNeurosurgery,
4bLudwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231;
5Otolaryngology-Head and Neck Surgery
6Christus Stehlin Foundation for Cancer Research, Houston, TX 77025;
7Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794;
8Molecular Oncology Laboratory, Department of Orthopaedic Surgery, University of Chicago Medical Center, Chicago, IL 60637;
9Pathology
10hPathology,
11Department of Clinical Genetics, Lund University Hospital, 221 85 Lund, Sweden
12mOncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231;
13Urology, and
14Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20852; and
15Comprehensive Cancer Center, University of Colorado, Aurora, CO 80045
Tóm tắt
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.
