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Updated: Sep 21, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune
ByulA Jee1, Eunjeong Seo1, Kyunghee Park2
1Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea.
Abstract:
Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in PBRM1, a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of PBRM1 mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing (n = 60) and whole transcriptomic sequencing (WTS) (n = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of PBRM1 mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of PBRM1 mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of PBRM1 mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that GATM (glycine amidinotransferase), as a novel gene associated with PBRM1 mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene GATM can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs.
Insights
Clear cell renal cell carcinoma (ccRCC) subtypes reveal distinct responses to immune checkpoint inhibitors (ICIs). PBRM1 mutations and GATM gene expression are key factors influencing immunotherapy outcomes in ccRCC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Clear cell renal cell carcinoma (ccRCC) exhibits immune infiltration and angiogenesis, yet its response to immune checkpoint inhibitors (ICIs) is not fully understood.
- PBRM1 mutations are linked to better ICI response in ccRCC, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To characterize molecular subtypes of metastatic ccRCC and their association with clinical outcomes following ICI treatment.
- To investigate the functional role of PBRM1 mutations and identify novel genes, such as GATM, influencing immunotherapy response in ccRCC.
Main Methods:
- Targeted and whole transcriptomic sequencing (WTS) of 177 metastatic ccRCC tumors from patients treated with ICIs, including data from the CheckMate 025 trial.
- Bioinformatic analysis to identify molecular subtypes, assess PBRM1 mutation frequencies, and analyze gene expression patterns.
- Cell culture models to investigate the functional role of GATM in ccRCC.
Main Results:
- Three distinct molecular subtypes of ccRCC were identified, correlating with differential responses to ICIs.
- Subtypes 1 and 3 showed poor response and survival, characterized by low PBRM1 mutation, angiogenesis-poor, immune-rich, and cell-cycle enriched phenotypes.
- Subtype 2 exhibited better response and survival, associated with PBRM1 mutation enrichment, metabolic programs, and a less exhausted immune phenotype. GATM was identified as a novel gene linked to PBRM1 mutation, showing tumor-suppressive features.
Conclusions:
- Metastatic ccRCC exhibits distinct genomic and transcriptomic features that predict response to ICIs.
- The novel gene GATM may act as a tumor suppressor and is associated with therapeutic efficacy in ccRCC patients treated with ICIs.
