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Proteogenomic Analysis Identifies Clinically Relevant Subgroups of Collecting Duct Carcinoma
Yuanyuan Qu1,2, Xiaoru Pei1, Jinwen Feng1
1Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200433, China.
Abstract:
Collecting duct carcinoma (CDC) is a rare but aggressive form of renal cell carcinoma (RCC) that has limited understanding and an undefined systemic therapeutic regimen. Herein, we conducted a comprehensive proteogenomic analysis of CDC tumors and normal adjacent tissues to elucidate the biology of the disease. CDC exhibited high heterogeneity in tumor mutational burden, and enhanced ribosome biogenesis was the most striking malignant feature of CDC, even compared with other common kidney carcinomas. Genomic data indicated that UTP6 and HN1 amplification on chromosome 17q were associated with the activations of ribosome biogenesis and cell migration, respectively, which were relevant to tumor proliferation and metastasis. Proteomic-based classification identified 3 clusters, among which, tumors overexpressing ribosome biogenesis signaling (GP1) clustered into the most aggressive subtype, while tumors with increased energy metabolism (GP3) exhibited significant sensitivity to anti-vascular endothelial growth factor agents. Immune subtyping revealed a complex immune landscape of CDC. Additionally, increased RPF2, contributing to ribosome production, was validated to be associated with malignant phenotypes, and targeting RPF2 could exert an anti-oncogenic role by disrupting ribosome biogenesis and perturbing the MDM2-p53 interaction.
Insights
Collecting duct carcinoma (CDC) is a rare kidney cancer. Proteogenomic analysis reveals enhanced ribosome biogenesis as a key driver of CDC aggressiveness and metastasis, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Proteomics
Background:
- Collecting duct carcinoma (CDC) is a rare and aggressive subtype of renal cell carcinoma (RCC).
- Limited understanding exists regarding its underlying biology and effective systemic treatments.
- A comprehensive proteogenomic approach is needed to elucidate CDC pathogenesis.
Purpose of the Study:
- To conduct a comprehensive proteogenomic analysis of CDC tumors and adjacent normal tissues.
- To identify key molecular features driving CDC aggressiveness and potential therapeutic vulnerabilities.
- To understand the complex immune landscape within CDC tumors.
Main Methods:
- Proteogenomic analysis integrating genomic and proteomic data from CDC tumors and normal tissues.
- Assessment of tumor mutational burden and chromosomal amplifications (e.g., 17q).
- Proteomic-based and immune subtyping of tumors.
Main Results:
- CDC exhibits high tumor mutational burden heterogeneity.
- Enhanced ribosome biogenesis is a prominent malignant feature in CDC, surpassing other kidney carcinomas.
- UTP6 and HN1 amplifications correlate with ribosome biogenesis and cell migration, respectively.
- Proteomic subtypes revealed aggressive (GP1, ribosome biogenesis) and potentially sensitive (GP3, energy metabolism to anti-VEGF) groups.
- RPF2 overexpression is linked to malignant phenotypes and may be a therapeutic target.
Conclusions:
- Enhanced ribosome biogenesis is a critical driver of collecting duct carcinoma aggressiveness and metastasis.
- Specific genomic alterations (UTP6, HN1) and protein expression (RPF2) are associated with tumor progression.
- Proteomic and immune profiling reveals distinct subtypes and potential therapeutic strategies, including targeting ribosome biogenesis and anti-VEGF therapy.
