Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct Carcinoma
Chiara Gargiuli, Pierangela Sepe, Anna Tessari, Tyler Sheetz, Maurizio Colecchia, Filippo Guglielmo Maria de Braud, Giuseppe Procopio, Marialuisa Sensi, Elena Verzoni, Matteo Dugo, Chiara Gargiuli, Pierangela Sepe, Anna Tessari, Tyler Sheetz, Maurizio Colecchia, Filippo Guglielmo Maria de Braud, Giuseppe Procopio, Marialuisa Sensi, Elena Verzoni, Matteo Dugo
Abstract
Collecting duct carcinoma (CDC) is a rare and highly aggressive kidney cancer subtype with poor prognosis and no standard treatments. To date, only a few studies have examined the transcriptomic portrait of CDC. Through integration of multiple datasets, we compared CDC to normal tissue, upper-tract urothelial carcinomas, and other renal cancers, including clear cell, papillary, and chromophobe histologies. Association between CDC gene expression signatures and in vitro drug sensitivity data was evaluated using the Cancer Therapeutic Response Portal, Genomics of Drug Sensitivity in Cancer datasets, and connectivity map. We identified a CDC-specific gene signature that predicted in vitro sensitivity to different targeted agents and was associated to worse outcome in clear cell renal cell carcinoma. We showed that CDC are transcriptionally related to the principal cells of the collecting ducts providing evidence that this tumor originates from this normal kidney cell type. Finally, we proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Our findings elucidate the molecular features of CDC providing novel biological and clinical insights. The identification of distinct CDC subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches.
Keywords: collecting duct carcinoma; gene expression; histological classification; kidney cancer; molecular subtypes; prognostic/predictive biomarkers; renal cell carcinomas; transcriptomic.
Conflict of interest statement
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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