The molecular subtypes of metastatic urothelial carcinoma identified by whole genome and transcriptome sequencing

Researchers from the departments of urology and internal oncology of the Erasmus MC Cancer Institute, in collaboration with Hartwig Medical Foundation published a study in the leading journal European Urology (Impact Factor 20,096). The study describes the results of an extensive molecular analysis of patients with metastatic cancer of the urinary tract (urothelial cancer). The present study defined, for the first time, the molecular subtypes of metastatic urothelial carcinoma based on whole genome and transcriptome analysis of metastatic biopsies of 116 patients.

Summary of key findings

Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options available. A comprehensive molecular profiling of mUC is crucial for patient stratification and for the development of rational treatment strategies that will eventually improve the outcome of this lethal cancer. In this study, the researchers provide a comprehensive characterization of the genomic and transcriptomic landscape of mUC using whole genome DNA sequencing (WGS) data obtained from 116 patients and matched RNA sequencing data from 90 patients.

Mutational landscape

Analysis of significantly mutated genes revealed the genomic similarity between primary UC and mUC. Furthermore, WGS data allowed the identification of recurrent structural variants in CCSER1 (13%) and AHR (12%), as well as the identification of 71 promoters frequently mutated. The promoters of TERT (64%), LEPROTL1 (20%) and GSTA4 (14%) had the highest mutation rate.

Genomic subtypes

The distribution of mutations in 96-tri nucleotide context contains information regarding the mutagenic processes that a specific cancer has been exposed to. These mutational signatures were obtained using all single-based substitutions (SBS). The clustering of the proposed etiology of mutational signatures revealed two major genomic subtypes (GenS). GenS1 (67%) was APOBEC-driven with a large contribution of APOBEC-associated mutational signatures, while GenS2 (24%) aggregated predominantly tumors characterized by mutational signatures associated with reactive oxygen species and putative clock-like. These subtypes also resemble the two major genomic subtypes identified in primary UC.

Transcriptomic subtypes

Transcriptomic subtyping of primary UC has been extensively characterized, but subtyping of mUC has not been reported thus far. A recent consensus transcriptomic classifier developed for primary UC does not consider the transcriptomic differences inherited from the metastatic site of mUC samples, and could not be applied directly to the present metastatic cohort. To overcome this limitation, a de novo transcriptomic subtyping system specific for mUC was necessary. The new transcriptomic mUC subtyping system incorporates five transcriptomic subtypes. Each subtype had unique genomic and transcriptomic features. One subtype (12%) was enriched for patients previously treated with chemotherapy ad may represent a treatment resistance subtype.

Response to treatment

Response to treatment was available for some patients that were treated after the samples were obtained. The authors observed better response in patients having GenS1 than GenS2.  They also saw that the basal/squamous transcriptomic subtype had the poorest outcome. Finally, several potential therapeutic strategies were proposed based on characteristics of each transcriptomic subtype.

Reference article:

Alberto Nakauma-González, Maud Rijnders, Job van Riet, Michiel S. van der Heijden, Jens Voortman, Edwin Cuppen, Niven Mehra, Sandra van Wilpe, Sjoukje F. Oosting, L. Lucia Rijstenberg, Hans M. Westgeest, Ellen C. Zwarthoff, Ronald de Wit, Astrid A.M. van der Veldt, Harmen J.G. van de Werken, Martijn P.J. Lolkema, Joost L. Boormans. Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma.

European Urology (2022) https://doi.org/10.1016/j.eururo.2022.01.026

Jan 28, 2022