Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers

Ruhana R. Jeeta, Naheema S. Gordon, Laura Baxter, Anshita Goel, Boris Noyvert, Sascha Ott, Rebecca H. Boucher, Nada Humayun-Zakaria, Roland Arnold, Nicholas D. James, Maurice P. Zeegers, K. K. Cheng, Richard T. Bryan, Douglas G. Ward*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Web of Science)

Abstract

BACKGROUND & OBJECTIVE: Whole genome sequencing has identified recurrent non-coding mutations that may be important in carcinogenesis. We investigate the frequency of 5 such non-coding mutation hotspots in urothelial bladder cancers (UBCs) and assess their potential for UBC detection and prognostication.

METHODS: DNA extracted from 302 UBCs was subjected to targeted next generation sequencing of non-coding mutation hotspots in GPR126, PLEKHS1, TBC1D12, LEPROTL1 and WDR74. The frequency of mutations, and associations with stage, grade, age, gender, smoking status, clinical outcomes, mutation signatures and gene expression were analysed using chi(2) tests, logistic regression and Cox proportional hazards models.

RESULTS: Non-coding mutations were common across all stages and grades of UBC. The frequencies were: GPR126 53.0%, PLEKHS1 38.7%, TBC1D12 25.5%, LEPROTL1 23.8% and WDR74 17.2%. There was an average of 1.6 mutations per UBC, and 74% of UBCs harboured at least one mutation. They frequently co-occur, and commonly accompany an APOBEC mutational signature. The mutations are not strongly associated with clinical parameters and are, most likely, early events in the development of UBC.

CONCLUSIONS: Mutations at these 5 non-coding hotspots are common in UBC. Due to their high frequency across stages and grades of disease, they should be included in UBC diagnostic biomarker panels.

Original languageEnglish
Pages (from-to)263-272
Number of pages10
JournalBladder Cancer
Volume5
Issue number4
DOIs
Publication statusPublished - 2019

Keywords

  • Bladder cancer
  • non-coding
  • mutations
  • prognosis
  • detection
  • DNA
  • TERT PROMOTER MUTATIONS
  • REGULATORY MUTATIONS
  • RECURRENT

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