title: Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation.
abstract: BACKGROUND
  Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations.
  
  
  METHODS
  TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay.
  
  
  RESULTS
  TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter.
  
  
  CONCLUSIONS
  TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets.
authors.affiliation: Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Huang
authors.affiliation: The 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, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Xu-Jun
authors.initials: XJ
authors.lastname: He
authors.affiliation: The 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, USA.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Diplas
authors.affiliation: The 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, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: The 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, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Killela
authors.affiliation: Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Zai-Yuan
authors.initials: ZY
authors.lastname: Ye
authors.affiliation: Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: He
authors.affiliation: Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Zhong-Sheng
authors.initials: ZS
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Xu
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Ma
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Xia
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Ru-Xuan
authors.initials: RX
authors.lastname: Zhang
authors.affiliation: Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jin
authors.affiliation: Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Zhong-Kuo
authors.initials: ZK
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yu
authors.affiliation: Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Junbo
authors.initials: J
authors.lastname: Liang
authors.affiliation: Genetron Health (Beijing) Technology, Co. Ltd., D101, Building 33, KeChuang 14th Street #99, JingHai 1 Road, Economic and Technological Development Area, Beijing, China.
authors.forename: Sizhen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Institute & Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: jiaoyuchen@cicams.ac.cn.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: The 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, USA. Electronic address: hai.yan@dm.duke.edu.
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China. Electronic address: taohouquan2008@aliyun.com.
authors.forename: Hou-Quan
authors.initials: HQ
authors.lastname: Tao
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: China; Genetics; Glioma; Neoplasms; Promoter regions; Telomerase
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