Abstract 2190: Integrative genomic and transcriptomic characterization of metastatic urothelial carcinoma
Authors: Rijnders Maud , Nakauma-González J Alberto , van Riet Job , van der Heijden Michiel S. , Voortman Jens , Cuppen Edwin P. J. G , Mehra Niven , van Wilpe Sandra , Oosting Sjoukje F. , Rijstenberg L Lucia , Zwarthoff Ellen C. , de Wit Ronald , van der Veldt Astrid A. , van de Werken Harmen J. , Lolkema Martijn P. , Boormans Joost L. 
Published: July 2021

Abstract
Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options available. To identify novel targets for therapy, large-scale sequencing efforts are needed. The Cancer Genome Atlas (TCGA) initiative substantially improved our knowledge on the genomic and transcriptomic characteristics of primary UC (Robertson et al. Cell 2017), however, the molecular landscape of mUC still remains largely unexplored.
We performed whole genome sequencing (WGS) on 116 biopsies of UC metastases and matched mRNA sequencing (RNAseq) for 90 samples. We applied genomic alteration analysis on the WGS data and consensus clustering on the RNAseq data.
We compared the molecular alterations of mUC with the data of the TCGA cohort and found that most affected driver genes were similar between primary UC and mUC. However, we identified CNTNAP5, RARG and MGP as exclusively mutated driver genes in the metastatic setting, and TP53 alterations were more prevalent in mUC than in primary UC. APOBEC induced mutation signatures in coding and non-coding regions were identified in 91% of the mUC samples and correlated with ploidy, mutational burden and copy number alterations. Based on the etiology of observed mutational signatures, five genomic subtypes were identified in mUC and validated in the TCGA cohort. APOBEC mutagenesis was the main mutational process in genomic subtype 1, which was the most common subtype (67%, N = 78). Moreover, APOBEC deamination mutations were found to be increased over time in paired biopsies from eight patients, indicating that APOBEC enzyme activity is ongoing in the metastatic setting. Unsupervised clustering and comparing phenotypic markers between the groups revealed five clinically-relevant transcriptomic subtypes: luminal-a (20%), luminal-b (20%), stroma-rich (24%), basal/squamous (23%) and a non-specified phenotype (12%). The basal/squamous and stroma-rich subtypes showed highly similar molecular characteristics as the TCGA subtypes, but with enrichment of the stroma-rich and reduction of the basal/squamous subtype. Based on genomic alterations, potential therapeutic targets were identified in 111/116 mUC patients, of which FGFR3 alterations (18%) and fusions (6%), and CDKN2A (44%), ERBB2 (20%), and TSC1 (14%) alterations were most common. By integrating the genomic and transcriptomic data, we propose potential novel therapeutic options per transcriptomic subtype, like addition of a TGF-β inhibitor to immune checkpoint inhibition for the stroma-rich and basal/squamous subtypes that showed the highest TGF-β pathway activity.
Using WGS and RNAseq analyses, we provide a comprehensive overview of the molecular landscape of mUC that may serve as a reference for more subgroup-oriented and patient-specific research on the etiology of mUC and future drug development.
Citation Format: Maud Rijnders, J Alberto Nakauma-González, Job van Riet, Michiel S. van der Heijden, Jens Voortman, Edwin P. J. G Cuppen, Niven Mehra, Sandra van Wilpe, Sjoukje F. Oosting, L Lucia Rijstenberg, Ellen C. Zwarthoff, Ronald de Wit, Astrid A. van der Veldt, Harmen J. van de Werken, Martijn P. Lolkema, Joost L. Boormans. Integrative genomic and transcriptomic characterization of metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2190.