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Eur J Cancer. 2015 May;51(8):969-76. doi: 10.1016/j.ejca.2015.03.010. Epub 2015 Apr 2.

Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation.

Author information

1
Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
2
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.
3
Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China.
4
Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, China.
5
Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
6
Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
7
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
8
Genetron Health (Beijing) Technology, Co. Ltd., D101, Building 33, KeChuang 14th Street #99, JingHai 1 Road, Economic and Technological Development Area, Beijing, China.
9
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.
10
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.
11
Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China. Electronic address: taohouquan2008@aliyun.com.

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.

KEYWORDS:

China; Genetics; Glioma; Neoplasms; Promoter regions; Telomerase

PMID:
25843513
PMCID:
PMC4467782
DOI:
10.1016/j.ejca.2015.03.010
[Indexed for MEDLINE]
Free PMC Article
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