Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

Abstract

Metastatic urothelial carcinoma (mUC) is a lethal cancer for which few therapeutic options exist. To define the molecular landscape of mUC and to identify targets for therapy, we performed whole genome DNA- and RNA-sequencing on fresh-frozen metastatic tumor biopsies of 116 mUC patients. Driver genes resembled those reported for primary UC; yet, three putative driver genes unique to mUC were identified: CNTNAP5, RARG and MGP. Consensus clustering based on mutational signatures revealed two major genomic subtypes. The most prevalent subtype (67%) consisted almost exclusively of tumors with high APOBEC mutagenesis. Five RNA-based subtypes were identified, of which four resembled those reported for primary UC, and one had a non-specified phenotype. By integrating the genomic and transcriptomic data potential therapeutic options per subtype and individual patient are proposed. This study serves as a reference for subtype-oriented and patient-specific research on the etiology of mUC, and for novel drug development.

Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer

“…Genomic analyses of bladder cancer of various stages and grades have shown that bladder cancer is a heterogeneous disease of which the high mutation burden is largely driven by activation of APOBEC mutagenesis (Lawson et al 2020;Nakauma-González et al 2021;Robertson et al 2018). Molecular characterization revealed activating FGFR3 alterations in ~16% of the samples, with a higher prevalence in non-muscle invasive bladder cancer (Cancer Genome Atlas Research Network 2014; Robertson et al 2018).…”

Structural variation in genomes and its role in disease

“…Genome analyses of bladder cancer of various stages and grades have shown that bladder cancer is a heterogeneous disease of which the high mutation burden is largely driven by activation of APOBEC mutagenesis [115][116][117] . Molecular characterization revealed in 16-17% of the samples FGFR3 alterations, with higher prevalence in NMIBC 117,118 .…”