Abstract
Metastatic urothelial carcinoma (mUC) is a lethal cancer for which few therapeutic options exist. To define the molecular landscape of mUC and to identify targets for therapy, we performed whole genome DNA- and RNA-sequencing on fresh-frozen metastatic tumor biopsies of 116 mUC patients. Driver genes resembled those reported for primary UC; yet, three putative driver genes unique to mUC were identified: CNTNAP5, RARG and MGP. Consensus clustering based on mutational signatures revealed two major genomic subtypes. The most prevalent subtype (67%) consisted almost exclusively of tumors with high APOBEC mutagenesis. Five RNA-based subtypes were identified, of which four resembled those reported for primary UC, and one had a non-specified phenotype. By integrating the genomic and transcriptomic data potential therapeutic options per subtype and individual patient are proposed. This study serves as a reference for subtype-oriented and patient-specific research on the etiology of mUC, and for novel drug development.
Competing Interest Statement
Michiel S. van der Heijden has received research support from Bristol-Myers Squibb, AstraZeneca and Roche, and consultancy fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Seattle Genetics and Janssen (all paid to the Netherlands Cancer Institute). Niven Mehra has received research support from Astellas, Janssen, Pfizer, Roche and Sanofi Genzyme, and consultancy fees from Roche, MSD, BMS, Bayer, Astellas and Janssen (all paid to the Radboud University Medical Center). Sjoukje F. Oosting has received research support from Celldex and Novartis (both paid to the University Medical Center Groningen). Hans M. Westgeest has received consultancy fees from Roche and Astellas (all paid to the Amphia hospital, Breda), Ronald de Wit has received research support from Sanofi and Bayer, and consultancy fees from Sanofi, Merck, Astellas, Bayer, Janssen, and Roche (all paid to the Erasmus MC Cancer Institute). Astrid A.M. van der Veldt has received consultancy fees from for BMS, MSD, Merck, Novartis, Roche, Sanofi, Pierre Fabre, Ipsen, Eisai, Pfizer (all paid to the Erasmus MC Cancer Institute). Martijn P. J. Lolkema has received research support from JnJ, Sanofi, Astella and MSD, and personal fees from Incyte, Amgen, JnJ, Bayer, Servier, Roche, INCa, Pfizer, Sanofi, Astellas, AstraZeneca, MSD, Novartis and Julius Clinical (all paid to the Erasmus MC Cancer Institute). Joost L. Boormans has received research support from Decipher Biosciences and Merck Sharp & Dohme, and consultancy fees from Merck Sharp & Dohme, Eight Medical, Ambu, APIM therapeutics and Janssen (all paid to the Erasmus MC Cancer Institute). J. Alberto Nakauma-Gonzalez, Maud Rijnders, Job van Riet, Jens Voortman, Edwin Cuppen, Sandra van Wilpe, L. Lucia Rijstenberg, Ellen C. Zwarthoff, and Harmen J. G. van de Werken declare no competing interests.
Footnotes
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