title: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.
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.
authors.affiliation: Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Killela
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.forename: Beppino C
authors.initials: BC
authors.lastname: Giovanella
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: George I
authors.initials: GI
authors.lastname: Jallo
authors.forename: Nils
authors.initials: N
authors.lastname: Mandahl
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.forename: B Ahmed
authors.initials: BA
authors.lastname: Rasheed
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rosenquist
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000648:ultrastructure; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase