The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma

被引：120

作者：

Diplas, Bill H. ^{[1
,2
]}

He, Xujun ^{[1
,2
,3
]}

Brosnan-Cashman, Jacqueline A. ^{[4
]}

Liu, Heng ^{[1
,2
]}

Chen, Lee H. ^{[1
,2
]}

Wang, Zhaohui ^{[1
,2
]}

Moure, Casey J. ^{[1
,2
]}

Killela, Patrick J. ^{[1
,2
]}

Loriaux, Daniel B. ^{[1
,2
]}

Lipp, Eric S. ^{[1
]}

Greer, Paula K. ^{[1
,2
]}

Yang, Rui ^{[1
,2
]}

Rizzo, Anthony J. ^{[4
]}

Rodriguez, Fausto J. ^{[4
]}

Friedman, Allan H. ^{[1
,5
]}

Friedman, Henry S. ^{[1
]}

Wang, Sizhen ^{[6
]}

He, Yiping ^{[1
,2
]}

McLendon, Roger E. ^{[1
,2
]}

Bigner, Darell D. ^{[1
,5
]}

Jiao, Yuchen ^{[7
,8
]}

Waitkus, Matthew S. ^{[1
,2
]}

Meeker, Alan K. ^{[4
]}

Yan, Hai ^{[1
,2
]}

机构：

[1] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA

[2] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA

[3] Zhejiang Prov Peoples Hosp, Hangzhou Med Coll, Key Lab Gastroenterol Zhejiang Prov, Hangzhou 310014, Zhejiang, Peoples R China

[4] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Pathol, Baltimore, MD 21231 USA

[5] Duke Univ, Med Ctr, Dept Neurosurg, Durham, NC 27710 USA

[6] Genetron Hlth Beijing Co Ltd, Beijing 102208, Peoples R China

[7] Chinese Acad Med Sci, Canc Hosp, Natl Canc Ctr, Lab Cell & Mol Biol,State Key Lab Mol Oncol, Beijing 100021, Peoples R China

[8] Peking Union Med Coll, Beijing 100021, Peoples R China

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

TELOMERE MAINTENANCE; MUTATIONS; SMARCAL1; CELLS; TUMORS; DNA; PHENOTYPE; BRAIN; ATRX; REARRANGEMENTS;

D O I：

10.1038/s41467-018-04448-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTp(WT)-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTp(WT)-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.

引用

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