Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct Carcinoma

SIMPLE SUMMARY: The treatment of collecting duct carcinoma (CDC) remains unsatisfactory since this highly aggressive kidney cancer has an unfavorable clinical behavior. Due to the rarity of CDC a complete biological characterization of this disease is still lacking. The aim of our study is to provide new insights into the molecular biology of CDC leveraging newly generated and publicly available gene expression profiles of CDC tumors. We identified unique gene expression programs and pathways that distinguished CDC from other renal malignancies. The CDC-specific expression signature predicted in vitro sensitivity to several small molecule inhibitors screened in cancer cell lines from multiple cancer types. Finally, we proved that CDC is a molecularly heterogeneous disease made up of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Altogether, these findings pave the way for future investigations with meaningful clinical implications aimed at improving the management of CDC patients. 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.