Pitie-Salpetriere Hospital, Paris, France
Gabriel G. Malouf , Eva Comperat , Hui Yao , Roger Mouawad , Veronique Lindner , Nathalie Rioux-Leclercq , Virginie Verkarre , Xavier Leroy , Linda Dainese , Marion Classe , Jean-Luc Descotes , Philippe Barthelemy , Mokrane Yacoub , Morgan Roupret , Jean-Christophe Bernhard , Chad J. Creighton , Jean-Philippe Spano , Xiaoping Su , David Khayat
Background: Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggest an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Furthermore, the transcriptomic profile of CDC is not fully known. Methods: CDC samples (n = 15) collected from several French institutions were centrally reviewed by a national expert pathologist. As a control, muscle-invasive UTUC samples (n = 10) were also analyzed. RNA sequencing of CDC was performed and compared to that of urothelial (UTUC and bladder) and renal cell carcinoma (RCC) subtypes (clear-cell, papillary, translocation and chromophobe). Tumor infiltrating lymphocytes (TIL) were also analyzed using CD4, CD8 and CD3 staining. Results: CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response. We found that the overall median TIL percentage in CDC assessed using CD3 staining was 22% (range: 0%-50%), with a higher statistically significant percentage in metastatic versus non-metastatic tumors (p = 0.04). Similarly, the median CD8 TIL percentage was 11% (range: 0%-25%), with a trend toward a higher percentage in metastatic versus non-metastatic tumors (p = 0.08). Genes and pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. Finally, we identified a set of genes wich might be used in clinic to differentiate between CDC and UTUC with good accuracy. Conclusions: CDC is unique among RCC subtypes that display a pathognomonic transcriptomic signature. Furthermore, CDC is both immunogenic and a metabolic disease, indicating that targeting these processes might provide therapeutic options for patients with CDC.
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