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Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct
Chiara Gargiuli1, Pierangela Sepe2, Anna Tessari3
1Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
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.
Insights
Collecting duct carcinoma (CDC) is a rare kidney cancer. This study identified a CDC gene signature predicting drug sensitivity and revealed CDC is a heterogeneous disease with distinct subtypes.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Collecting duct carcinoma (CDC) is a rare, aggressive kidney cancer subtype.
- Limited transcriptomic data exists for CDC, hindering treatment development.
- Current treatment options for CDC are not standardized.
Purpose of the Study:
- To elucidate the molecular and transcriptomic landscape of collecting duct carcinoma.
- To identify potential therapeutic targets and biomarkers for CDC.
- To investigate the cellular origin and heterogeneity of CDC.
Main Methods:
- Integration of multiple transcriptomic datasets comparing CDC to normal kidney tissue and other renal cancer types.
- Analysis of gene expression signatures using the Cancer Therapeutic Response Portal and Genomics of Drug Sensitivity in Cancer datasets.
- Comparative transcriptomic analysis to determine cellular origin and identify molecular subtypes.
Main Results:
- A novel CDC-specific gene signature was identified, predicting in vitro sensitivity to targeted therapies.
- This signature was associated with poorer outcomes in clear cell renal cell carcinoma.
- Transcriptomic data supports CDC originating from collecting duct principal cells.
- CDC was confirmed as a molecularly heterogeneous disease with at least two distinct subtypes characterized by altered cell signaling, metabolism, and immune response.
Conclusions:
- This study provides comprehensive molecular insights into collecting duct carcinoma.
- The identified CDC subtypes and transcriptomic traits offer a basis for patient stratification.
- Novel therapeutic strategies and targeted treatments can be developed based on these findings.
