Journal Article

The genomic and transcriptomic landscape of metastastic urothelial cancer

Neuzillet, Yann, Gutman, Tom, Syx, Laurene, Lavaud, Pernelle, Duquesne, Igor, Nicotra, Claudio, Borcoman, Edith, Dureau, Sylvain, Menssouri, Naoual, Besse, Benjamin, Radvanyi, Francois, Wong, Jennifer, Friboulet, Luc, Castel-Ajgal, Zahra, Lacroix, Ludovic, Tselikas, Lambros, Scoazec, Jean-Yves, Le tourneau, Christophe, Ngocamus, Maud, Beuzeboc, Philippe, Bieche, Ivan, Dupain, Celia, Allory, Yves, Loriot, Yohann, Servant, Nicolas, Andre, Fabrice, Massard, Christophe, Nicolle, Remy, Crehange, Gilles, Marret, Grégoire, Kamal, Maud

2024

Overview

Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases. Metastasis of urothelial carcinoma remains incurable due to insufficient treatment options for advanced disease. Here, the authors combine whole exome sequencing and RNA-seq from metastatic biopsies, and show temporal evolution when compared with primary tumour.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/39 / 38/91 / 45 / 45/23 / 631/67/589 / 631/67/69 / Aged / Aged, 80 and over / Antigens, Neoplasm - genetics / Antigens, Neoplasm - metabolism / APOBEC Deaminases - genetics / APOBEC Deaminases - metabolism / Biopsy / Cancer / Carcinoma, Transitional Cell - genetics / Carcinoma, Transitional Cell - pathology / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - metabolism / Class I Phosphatidylinositol 3-Kinases - genetics / Class I Phosphatidylinositol 3-Kinases - metabolism / Cytidine Deaminase - genetics / Cytidine Deaminase - metabolism / ErbB-2 protein / Exome Sequencing / Female / Fibroblast growth factor receptors / Gene Expression Profiling - methods / Gene Expression Regulation, Neoplastic / Gene sequencing / Genomics / Heterogeneity / Humanities and Social Sciences / Humans / Male / Metastases / Metastasis / Middle Aged / multidisciplinary / Mutation / Nectins - genetics / Nectins - metabolism / Neoplasm Metastasis - genetics / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Receptor, Fibroblast Growth Factor, Type 3 - metabolism / Science / Science (multidisciplinary) / Therapeutic targets / Transcriptome / Transcriptomics / Tuberous Sclerosis Complex 1 / Tuberous Sclerosis Complex 1 Protein - genetics / Tuberous Sclerosis Complex 1 Protein - metabolism / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - pathology / Urologic Neoplasms - genetics / Urologic Neoplasms - pathology / Urological cancer / Urothelial cancer / Urothelial carcinoma / Urothelium - metabolism / Urothelium - pathology / Whole genome sequencing