Comprehensive integrative profiling of upper tract urothelial carcinomas

Genome Biol. 2021 Jan 4;22(1):7. doi: 10.1186/s13059-020-02230-w.


Background: Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood.

Results: We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes.

Conclusions: Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.

Keywords: DNA methylation; Epigenetics; Immunity; SWI/SNF gene mutations; Sequencing; Upper tract urothelial carcinomas; ZFP36L1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Butyrate Response Factor 1 / genetics
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / immunology
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenomics
  • Gene Expression Regulation, Neoplastic*
  • Histone Demethylases / genetics
  • Humans
  • Immunity
  • Mutation
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Transcription Factors / genetics
  • Transcriptome
  • Tristetraprolin / genetics
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / immunology


  • Butyrate Response Factor 1
  • Transcription Factors
  • Tristetraprolin
  • ZFP36 protein, human
  • ZFP36L1 protein, human
  • ZFP36L2 protein, human
  • Histone Demethylases
  • KDM6A protein, human
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3