TY - JOUR
T1 - Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma
AU - Nakauma-González, J. Alberto
AU - Rijnders, Maud
AU - van Riet, Job
AU - van der Heijden, Michiel S.
AU - Voortman, Jens
AU - Cuppen, Edwin
AU - Mehra, Niven
AU - van Wilpe, Sandra
AU - Oosting, Sjoukje F.
AU - Rijstenberg, L. Lucia
AU - Westgeest, Hans M.
AU - Zwarthoff, Ellen C.
AU - de Wit, Ronald
AU - van der Veldt, Astrid A. M.
AU - van de Werken, Harmen J. G.
AU - Lolkema, Martijn P. J.
AU - Boormans, Joost L.
N1 - Funding Information: Funding/Support and role of the sponsor: This research was funded by the Barcode for Life Foundation through a grant to Martijn P.J. Lolkema. Harmen J.G. van de Werken, J. Alberto Nakauma-González, and the Erasmus MC Cancer Computational Biology Center were financed through a grant from the Daniel den Hoed Foundation and the Dutch Uro-Oncology Study group. This study was also partly financed by a grant from Merck Sharpe & Dome (Kenilworth, NJ, USA) to Martijn P.J. Lolkema. The sponsors had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Funding Information: Financial disclosures: Joost L. Boormans certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michiel S. van der Heijden has received institutional research support from Bristol-Myers Squibb, AstraZeneca, and Roche, and institutional consultancy fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Seattle Genetics, and Janssen. Niven Mehra has received institutional research support from Astellas, Janssen, Pfizer, Roche, and Sanofi Genzyme, and institutional consultancy fees from Roche, MSD, BMS, Bayer, Astellas, and Janssen. Sjoukje F. Oosting has received institutional research support from Celldex and Novartis. Hans M. Westgeest has received institutional consultancy fees from Roche and Astellas. Ronald de Wit has received institutional research support from Sanofi and Bayer, and institutional consultancy fees from Sanofi, Merck, Astellas, Bayer, Janssen, and Roche. Astrid A.M. van der Veldt has received institutional consultancy fees from BMS, MSD, Merck, Novartis, Roche, Sanofi, Pierre Fabre, Ipsen, Eisai, and Pfizer. Martijn P.J. Lolkema has received institutional research support from Johnson & Johnson, Sanofi, Astellas, and MSD, and institutional personal fees from Incyte, Amgen, Johnson & Johnson, Bayer, Servier, Roche, INCa, Pfizer, Sanofi, Astellas, AstraZeneca, MSD, Novartis, and Julius Clinical. Joost L. Boormans has received institutional research support from Decipher Biosciences and Merck Sharp & Dohme, and institutional consultancy fees from Merck Sharp & Dohme, Eight Medical, Ambu, APIM Therapeutics, BMS, and Janssen. J. Alberto Nakauma-González, 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 have nothing to disclose. Publisher Copyright: © 2022 The Authors
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive molecular characterization is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen metastatic tumor biopsies from 116 mUC patients who were scheduled for palliative systemic treatment within the context of a clinical trial (NCT01855477 and NCT02925234). Hierarchical clustering for mutational signatures revealed two major genomic subtypes: GenS1 (67%), which was APOBEC-driven; and GenS2 (24%), which had a high fraction of de novo mutational signatures related to reactive oxygen species and is putatively clock-like. Significantly mutated genes (SMGs) did not differ between the genomic subtypes. Transcriptomic analysis revealed five mUC subtypes: luminal-a and luminal-b (40%), stroma-rich (24%), basal/squamous (23%), and a nonspecified subtype (12%). These subtypes differed regarding expression of key genes, SMGs, oncogenic pathway activity, and immune cell infiltration. We integrated the genomic and transcriptomic data to propose potential therapeutic options by transcriptomic subtype and for individual patients. This in-depth analysis of a large cohort of patients with mUC may serve as a reference for subtype-oriented and patient-specific research on the etiology of mUC and for novel drug development. Patient summary: We carried out an in-depth analysis of the molecular and genetic features of metastatic cancer involving the cells that line the urinary tract. We showed that this is a heterogeneous disease with different molecular subtypes and we identified possible targets for therapy for each subtype.
AB - Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive molecular characterization is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen metastatic tumor biopsies from 116 mUC patients who were scheduled for palliative systemic treatment within the context of a clinical trial (NCT01855477 and NCT02925234). Hierarchical clustering for mutational signatures revealed two major genomic subtypes: GenS1 (67%), which was APOBEC-driven; and GenS2 (24%), which had a high fraction of de novo mutational signatures related to reactive oxygen species and is putatively clock-like. Significantly mutated genes (SMGs) did not differ between the genomic subtypes. Transcriptomic analysis revealed five mUC subtypes: luminal-a and luminal-b (40%), stroma-rich (24%), basal/squamous (23%), and a nonspecified subtype (12%). These subtypes differed regarding expression of key genes, SMGs, oncogenic pathway activity, and immune cell infiltration. We integrated the genomic and transcriptomic data to propose potential therapeutic options by transcriptomic subtype and for individual patients. This in-depth analysis of a large cohort of patients with mUC may serve as a reference for subtype-oriented and patient-specific research on the etiology of mUC and for novel drug development. Patient summary: We carried out an in-depth analysis of the molecular and genetic features of metastatic cancer involving the cells that line the urinary tract. We showed that this is a heterogeneous disease with different molecular subtypes and we identified possible targets for therapy for each subtype.
KW - Molecular profiling
KW - Neoplasm metastases
KW - RNA sequencing
KW - Urologic neoplasms
KW - Whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85123366968&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.eururo.2022.01.026
DO - https://doi.org/10.1016/j.eururo.2022.01.026
M3 - Article
C2 - 35086719
SN - 0302-2838
VL - 81
SP - 331
EP - 336
JO - European Urology
JF - European Urology
IS - 4
ER -