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

P. Sivaramakrishna Rachakonda, Ismail Hosen, Petra J. De Verdier, Mahdi Fallah, Barbara Heidenreich, Charlotta Ryk, N. Peter Wiklund, Gunnar Steineck, Dirk Schadendorf, Kari Hemminki, Rajiv Kumar

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

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.

Original languageEnglish
Pages (from-to)17426-17431
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
StatePublished - 22 Oct 2013
Externally publishedYes

Keywords

  • Cancer genetics
  • Noncoding mutations
  • Reporter assays
  • TERT mutations
  • Transcription factors

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