The genomic and transcriptomic landscape of metastastic urothelial cancer

Auteurs

Yohann Loriot,

Maud Kamal,

Laurene Syx,

Nicolle Rémy,

Celia Dupain,

Naoual Mensourri,

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 Le Tourneau,

Christophe Massard,

Ivan Bieche,

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.

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[:fr]C. Saillard[:],

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