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Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer

Hosen, Ismail; Rachakonda, P. Sivaramakrishna; Heidenreich, Barbara; de Verdier, Petra J.; Ryk, Charlotta; Steineck, Gunnar; Hemminki, Kari LU and Kumar, Rajiv (2015) In International Journal of Cancer 137(7). p.1621-1629
Abstract
Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR)=4.93, 95% CI=2.72-8.92, p<0.0001]. While tumors with TERT promoter and FGFR3 mutations had... (More)
Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR)=4.93, 95% CI=2.72-8.92, p<0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p<0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR=2.15, 95% CI=1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR=3.68, 95%CI=1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target. What's New? The identification of recurrent somatic mutations in bladder cancer opens the door to the development of new prognostic and therapeutic tools. Here, the TERT promoter mutations in conjunction with a common variant, rs2853669, define a subset of patients with increased risk of recurrence and poor survival. Mutations in FGFR3, in contrast, were not independently associated with either disease recurrence or overall survival. Tumors with mutations in FGFR3 or the TERT promoter carried shorter telomeres than those without mutations. The findings highlight the prognostic potential of TERT mutations and reveal a possible etiological role for telomere biology in bladder cancer. (Less)
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author
organization
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Contribution to journal
publication status
published
subject
keywords
TERT promoter, teleomere length, FGFR3, bladder cancer
in
International Journal of Cancer
volume
137
issue
7
pages
1621 - 1629
publisher
John Wiley & Sons
external identifiers
  • wos:000358012600010
  • scopus:84943404744
ISSN
0020-7136
DOI
10.1002/ijc.29526
language
English
LU publication?
yes
id
d53f04af-5b09-4890-bd88-33b7b7ee2ca7 (old id 7779695)
date added to LUP
2015-09-01 16:06:16
date last changed
2017-10-22 03:17:07
@article{d53f04af-5b09-4890-bd88-33b7b7ee2ca7,
  abstract     = {Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR)=4.93, 95% CI=2.72-8.92, p&lt;0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p&lt;0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR=2.15, 95% CI=1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR=3.68, 95%CI=1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target. What's New? The identification of recurrent somatic mutations in bladder cancer opens the door to the development of new prognostic and therapeutic tools. Here, the TERT promoter mutations in conjunction with a common variant, rs2853669, define a subset of patients with increased risk of recurrence and poor survival. Mutations in FGFR3, in contrast, were not independently associated with either disease recurrence or overall survival. Tumors with mutations in FGFR3 or the TERT promoter carried shorter telomeres than those without mutations. The findings highlight the prognostic potential of TERT mutations and reveal a possible etiological role for telomere biology in bladder cancer.},
  author       = {Hosen, Ismail and Rachakonda, P. Sivaramakrishna and Heidenreich, Barbara and de Verdier, Petra J. and Ryk, Charlotta and Steineck, Gunnar and Hemminki, Kari and Kumar, Rajiv},
  issn         = {0020-7136},
  keyword      = {TERT promoter,teleomere length,FGFR3,bladder cancer},
  language     = {eng},
  number       = {7},
  pages        = {1621--1629},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer},
  url          = {http://dx.doi.org/10.1002/ijc.29526},
  volume       = {137},
  year         = {2015},
}