Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Targeted Sequencing Preprocess
2.3. RNA-Sequencing Preprocess
2.4. Immunohistochemical Analysis
2.5. GSEA (Gene Set Enrichment Analysis) and ssGSEA (Single-Sample GSEA)
2.6. Immune Cell Type and Immune Type
2.7. The Signatures of Differentially Expressed Genes (DEGs)
2.8. Statistical Analysis
2.9. Validation Sets
2.10. Cell Culture and Treatments
2.11. Real-Time qPCR
2.12. Cell Migration Assays
2.13. Colony Formation Assay
3. Results
3.1. The Characteristics of Genomic Alterations in Patients with ccRCC Treated with ICIs
3.2. The Characteristics of Molecular Subtypes in Patients with ccRCC Treated with ICIs
3.3. Subtype 2 Is Associated with Higher Metabolic Processes and Lower Exhausted Immune Types than the Other Two Subtypes
3.4. GATM Expression Associated with PBRM1 Mutation as a Novel Biomarker of Therapeutic Response in Patients with ccRCC Treated by ICIs
3.5. GATM Protein Levels Using Immunohistochemistry Are Related to Favorable Survival
3.6. PBRM1 Deficiency and GATM Upregulation in Stress Conditions Reduce Cell Proliferation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Variables | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | ||
Age | <Median | Reference | - | Reference | - |
≥Median | 0.855 (0.58–1.26) | 0.428 | 0.895 (0.599–1.339) | 0.589 | |
Sex | Female | Reference | - | Reference | - |
Male | 2.047 (1.235–3.394) | 0.005 ** | 1.576 (0.939–2.645) | 0.085 | |
IMDC | Favor | Reference | - | Reference | - |
Intermediate & Poor | 2.134 (1.336–3.409) | 0.0015 ** | 2.012 (1.252–3.233) | 0.004 ** | |
PBRM1 & GATM | MUT & HIGH | Reference | - | Reference | - |
MUT & LOW, WT & HIGH, and WT & LOW | 2.532 (1.414–4.532) | 0.0017 ** | 2.067 (1.147–3.726) | 0.016 * |
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Jee, B.; Seo, E.; Park, K.; Kim, Y.R.; Byeon, S.-j.; Lee, S.M.; Chung, J.H.; Song, W.; Sung, H.H.; Jeon, H.G.; et al. Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma. Cancers 2022, 14, 2354. https://doi.org/10.3390/cancers14102354
Jee B, Seo E, Park K, Kim YR, Byeon S-j, Lee SM, Chung JH, Song W, Sung HH, Jeon HG, et al. Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma. Cancers. 2022; 14(10):2354. https://doi.org/10.3390/cancers14102354
Chicago/Turabian StyleJee, ByulA, Eunjeong Seo, Kyunghee Park, Yi Rang Kim, Sun-ju Byeon, Sang Min Lee, Jae Hoon Chung, Wan Song, Hyun Hwan Sung, Hwang Gyun Jeon, and et al. 2022. "Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma" Cancers 14, no. 10: 2354. https://doi.org/10.3390/cancers14102354