Telomerase reverse transcriptase gene promoter mutations help discern the origin of urogenital tumors: a genomic and molecular study.
Activation of telomerase can be observed in almost all human tumor histotypes and detection of the urinary telomerase activities is useful for the diagnosis and surveillance of bladder cancer. In this study, we screened, by Sanger sequencing, 302 patients with various urogenital cancers for somatic mutations in the promoter of the telomerase reverse transcriptase (TERT) gene and determined the clinical relevance of TERT promoter mutations in urogenital cancer. In vitro assays were also performed to evaluate the functional influence of the discovered mutations. We found that the frequencies of somatic mutations in the TERT promoter varied substantially between different types of urogenital tumors (range: 0-63.7%), with urothelial carcinomas showing the highest mutation frequency and prostate cancer showing no mutation. The mutations upregulated the expression of TERT and enhanced the invasiveness of the tumor cells. The mutations were more prevalent in older patients with invasive diseases and advanced tumor stages, and were associated with significantly shorter survival time. Moreover, we also observed a significant co-occurrence of mutations between the TERT promoter and the tumor protein 51/retinoblastoma1 (TP53/RB1) signaling pathway. Hence, TERT promoter mutations may serve as important markers for the differential diagnosis and surveillance of urogenital tumors.
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China; Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: doctor_wusong@126.com.
Song
S
Wu
Beijing Genomics Institute at Shenzhen, Shenzhen, China; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Peide
P
Huang
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China; CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Chong
C
Li
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Yi
Y
Huang
Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKUHKUST Medical Center, Shenzhen, China.
Xianxin
X
Li
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Yongqiang
Y
Wang
Beijing Genomics Institute at Shenzhen, Shenzhen, China.
Chao
C
Chen
Anhui Medical University, Hefei, China.
Zhaojie
Z
Lv
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Aifa
A
Tang
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Xiaojuan
X
Sun
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Jingxiao
J
Lu
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Weiping
W
Li
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Jie
J
Zhou
Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKUHKUST Medical Center, Shenzhen, China.
Yaoting
Y
Gui
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Fangjian
F
Zhou
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Daping
D
Wang
Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China. Electronic address: caizhiming2000@163.com.
Zhiming
Z
Cai
D019070:Cell Lineage / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics; D012307:Risk Factors; D019098:Telomerase / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014565:Urogenital Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase