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TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Rachakonda, P. Sivaramakrishna; Hosen, Ismail; de Verdier, Petra J.; Fallah, Mahdi; Heidenreich, Barbara; Ryk, Charlotta; Wiklund, N. Peter; Steineck, Gunnar; Schadendorf, Dirk and Hemminki, Kari LU , et al. (2013) In Proceedings of the National Academy of Sciences 110(43). p.17426-17431
Abstract
The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions - 124 and - 146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even... (More)
The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions - 124 and - 146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential. (Less)
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published
subject
keywords
TERT mutations, cancer genetics, transcription factors, noncoding, mutations, reporter assays
in
Proceedings of the National Academy of Sciences
volume
110
issue
43
pages
17426 - 17431
publisher
National Acad Sciences
external identifiers
  • wos:000325943300060
  • scopus:84886390673
ISSN
1091-6490
DOI
10.1073/pnas.1310522110
language
English
LU publication?
yes
id
eb69ab50-a9cb-4dbb-8857-97d35bc35694 (old id 4212778)
date added to LUP
2014-01-03 10:49:08
date last changed
2019-09-17 01:36:50
@article{eb69ab50-a9cb-4dbb-8857-97d35bc35694,
  abstract     = {The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions - 124 and - 146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.},
  author       = {Rachakonda, P. Sivaramakrishna and Hosen, Ismail and de Verdier, Petra J. and Fallah, Mahdi and Heidenreich, Barbara and Ryk, Charlotta and Wiklund, N. Peter and Steineck, Gunnar and Schadendorf, Dirk and Hemminki, Kari and Kumar, Rajiv},
  issn         = {1091-6490},
  keyword      = {TERT mutations,cancer genetics,transcription factors,noncoding,mutations,reporter assays},
  language     = {eng},
  number       = {43},
  pages        = {17426--17431},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism},
  url          = {http://dx.doi.org/10.1073/pnas.1310522110},
  volume       = {110},
  year         = {2013},
}