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Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis

Tadeusz Majewski1, Hui Yao2, Jolanta Bondaruk1

  • 1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cell Reports
|February 21, 2019
PubMed

Insights

DNA methylation changes initiate bladder cancer by creating a field effect, leading to mutations and copy number alterations. This study reveals DNA methylation as a key early driver in bladder carcinogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Multifocal bladder cancer presents complex locoregional molecular changes.
  • Understanding the early molecular events in bladder carcinogenesis is crucial.

Purpose of the Study:

  • To investigate the locoregional molecular alterations in human bladder cancer.
  • To identify the initiating events and pathways involved in bladder carcinogenesis.

Main Methods:

  • Whole-organ mapping of molecular changes in human bladder tissue.
  • Analysis of DNA methylation, mutations, and DNA copy alterations.
  • Identification of founder mutations and clonal expansion.

Main Results:

  • Widespread DNA methylation changes (field effect) were observed in the entire mucosa.
  • The field effect was linked to subclonal mutations and DNA copy alterations.
  • A founder mutation in ACIN1 initiated clonal expansion, preceding carcinoma development.
  • Mutations and copy number changes in carcinoma were clonally identical to in situ foci.
  • Affected pathways, including Kras, were preceded by DNA methylation changes.

Conclusions:

  • DNA methylation acts as an initiator of bladder carcinogenesis.
  • Field effect changes in DNA methylation precede and reinforce subsequent genetic alterations.
  • Understanding these early events can inform bladder cancer prevention and treatment strategies.
Keywords:
DNA copy alterationsDNA methylationWhole-organ mapbladder cancerclonal expansionclonal originsfield effectfounder mutationgene signatureurothelial carcinoma

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