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Identifying ADME-related gene signature for immune landscape and prognosis in KIRC by single-cell and spatial
Hongyun Wang1,2, Feizhou Li1, Qiong Wang2
1Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430061, China.
Abstract:
Kidney renal clear cell carcinoma (KIRC) is the most prevalent subtype of kidney cancer. Although multiple therapeutic agents have been proven effective in KIRC, their clinical application has been hindered by a lack of reliable biomarkers. This study focused on the prognostic value and function of drug absorption, distribution, metabolism, and excretion- (ADME-) related genes (ARGs) in KIRC to enhance personalized therapy. The critical role of ARGs in KIRC microenvironment was confirmed by single cell RNA-seq analysis and spatial transcriptome sequencing analysis for the first time. Then, an ADME-related prognostic signature (ARPS) was developed by the bulk RNA-seq analysis. The ARPS, created through Cox regression, LASSO, and stepAIC analyses, identified eight ARGs that stratified patients into high-risk and low-risk groups. High-risk patients had significantly poorer overall survival. Multivariate analysis confirmed the independent predictive ability of ARPS, and an ARPS-based nomogram was constructed for clinical application. Gene ontology and KEGG pathway analyses revealed immune-related functions and pathways enriched in these groups, with low-risk patients showing better responses to immunotherapy. Finally, the expression of ARGs was validated by qRT-PCR and Western blotting experiments. These findings underscore the prognostic significance of ARPS in KIRC and its potential application in guiding personalized treatment strategies.
Insights
This study identifies eight drug metabolism (ADME) genes as key biomarkers for predicting kidney cancer patient outcomes. This ADME-related prognostic signature (ARPS) can guide personalized treatment strategies and predict immunotherapy response.
Area of Science:
- Oncology
- Genomics
- Pharmacogenomics
Background:
- Kidney renal clear cell carcinoma (KIRC) is the most common kidney cancer subtype.
- Effective KIRC therapies exist, but reliable biomarkers for personalized treatment are lacking.
- Drug absorption, distribution, metabolism, and excretion (ADME)-related genes (ARGs) play a role in cancer progression and drug response.
Purpose of the Study:
- To investigate the prognostic value and function of ADME-related genes (ARGs) in KIRC.
- To develop a novel prognostic signature based on ARGs for KIRC patients.
- To explore the potential of this signature in guiding personalized therapy and predicting immunotherapy response.
Main Methods:
- Single-cell and spatial transcriptome sequencing to analyze ARGs in the KIRC microenvironment.
- Bulk RNA-sequencing data and statistical analyses (Cox regression, LASSO, stepAIC) to develop an ADME-related prognostic signature (ARPS).
- Gene Ontology and KEGG pathway analyses to identify enriched functions and pathways; qRT-PCR and Western blotting for validation.
Main Results:
- ARGs were confirmed to play a critical role in the KIRC microenvironment.
- An eight-gene ARPS was developed, effectively stratifying patients into high-risk and low-risk groups with distinct overall survival.
- High-risk patients exhibited significantly poorer survival; the ARPS demonstrated independent predictive ability and was used to construct a nomogram.
- Pathway analyses revealed immune-related functions, with low-risk patients showing better immunotherapy responses.
Conclusions:
- The developed ARPS holds significant prognostic value for KIRC.
- ARPS can potentially guide personalized treatment strategies and predict immunotherapy efficacy in KIRC patients.
- This study highlights the importance of ADME genes in KIRC prognosis and therapeutic decision-making.
