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

Ismail Hosen1, P Sivaramakrishna Rachakonda1, Barbara Heidenreich1

  • 1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.

International Journal of Cancer
|March 27, 2015
PubMed

Insights

Mutations in telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes are common in bladder cancer. These mutations, along with shorter telomeres, correlate with decreased survival and increased recurrence, suggesting TERT promoter mutations as potential therapeutic targets.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Urothelial carcinoma of the bladder frequently harbors mutations in the telomerase reverse transcriptase (TERT) promoter and fibroblast growth factor receptor 3 (FGFR3) genes.
  • These genetic alterations are among the most common somatic changes observed in bladder cancer.

Purpose of the Study:

  • To investigate the co-occurrence of TERT promoter and FGFR3 mutations in urothelial bladder carcinomas.
  • To assess the relationship between these mutations, relative telomere length (RTL), and clinical outcomes, including overall survival and disease recurrence.
  • To explore the potential of TERT promoter mutations as predictive biomarkers and therapeutic targets.

Main Methods:

  • Screening of DNA from 327 urothelial bladder carcinomas for FGFR3 alterations.
  • Analysis of known TERT promoter mutational status and measurement of relative telomere length (RTL).
  • Statistical analysis, including Odds Ratios (OR) and confidence intervals (CI), to evaluate mutation co-occurrence and clinical associations.

Main Results:

  • TERT promoter and FGFR3 alterations occurred together more frequently than expected by chance (OR = 4.93).
  • Tumors with TERT promoter and/or FGFR3 mutations exhibited shorter relative telomere lengths (RTL) compared to tumors without these mutations (p < 0.0001).
  • TERT promoter mutations, particularly with the rs2853669 polymorphism, were associated with decreased overall survival (OR = 2.15) and increased recurrence in specific disease categories (OR = 3.68).

Conclusions:

  • The co-occurrence of TERT promoter and FGFR3 mutations and their association with shorter telomeres suggest a mechanistic link to bladder cancer progression.
  • TERT promoter mutations show potential as biomarkers for refining patient selection for treatment strategies.
  • The high frequency of TERT promoter mutations supports their consideration as a future therapeutic target in bladder cancer.
Keywords:
FGFR3TERT promoterbladder cancerteleomere length

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