The genomic and transcriptomic landscape of metastastic urothelial cancer

Yohann Loriot (), Maud Kamal (), Laurene Syx, Remy Nicolle, Celia Dupain, Naoual Menssouri, Igor Duquesne, Pernelle Lavaud, Claudio Nicotra, Maud Ngocamus, Ludovic Lacroix, Lambros Tselikas, Gilles Crehange, Luc Friboulet, Zahra Castel-Ajgal, Yann Neuzillet, Edith Borcoman, Philippe Beuzeboc, Grégoire Marret, Tom Gutman, Jennifer Wong, Francois Radvanyi, Sylvain Dureau, Jean-Yves Scoazec, Nicolas Servant, Yves Allory, Benjamin Besse, Fabrice Andre, Christophe Tourneau, Christophe Massard and Ivan Bieche
Additional contact information
Yohann Loriot: Gustave Roussy
Maud Kamal: Institut Curie
Laurene Syx: INSERM U900
Remy Nicolle: F-
Celia Dupain: Institut Curie
Naoual Menssouri: Gustave Roussy
Igor Duquesne: Gustave Roussy
Pernelle Lavaud: Gustave Roussy
Claudio Nicotra: Gustave Roussy
Maud Ngocamus: Gustave Roussy
Ludovic Lacroix: Gustave Roussy
Lambros Tselikas: Gustave Roussy
Gilles Crehange: 75005 Paris & 92210 Saint-Cloud
Luc Friboulet: Gustave Roussy
Zahra Castel-Ajgal: Institut Curie
Yann Neuzillet: Foch Hospital
Edith Borcoman: Institut Curie
Philippe Beuzeboc: Foch Hospital
Grégoire Marret: Institut Curie
Tom Gutman: INSERM U900
Jennifer Wong: Institut Curie
Francois Radvanyi: Institut Curie
Sylvain Dureau: Institut Curie
Jean-Yves Scoazec: Gustave Roussy
Nicolas Servant: INSERM U900
Yves Allory: PSL Research University
Benjamin Besse: Gustave Roussy
Fabrice Andre: Gustave Roussy
Christophe Tourneau: Institut Curie
Christophe Massard: Gustave Roussy
Ivan Bieche: Institut Curie

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52915-0

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