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Updated: Oct 1, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
The genomic landscape of metastatic clear cell renal cell carcinoma after systemic therapy
Johannes C van der Mijn1,2,3, Kenneth W Eng3,4,5, Pooja Chandra3,4,5
1Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
Abstract:
Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed whole exome sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated genes in the metastatic ccRCC cohort. RBM10 and FBXW7 were also among the 10 most frequently mutated genes in metastatic tissues. Recurrent somatic copy number variations (CNV) were observed at the previously identified regions 3p25, 9p21 and 14q25, but also at 6p21 (CDKN1A) and 13q14 (RB1). No statistically significant differences were found between samples from therapy-naïve and pretreated patients. Clonal evolution analyses with multiple samples from 13 patients suggested that early appearance of CNVs at 3p25, 9p21 and 14q25 may be associated with rapid clinical progression. Overall, the genomic landscapes of primary and metastatic ccRCC seem to share frequent CNVs at 3p25, 9p21 and 14q25. Future work will clarify the implication of RBM10 and FBXW7 mutations and 6p21 and 13q14 CNVs in metastatic ccRCC.
Insights
The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) was explored using whole exome sequencing. Key mutations in SETD2, PBRM1, APC, and VHL were identified, alongside copy number variations potentially linked to disease progression.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Clear cell renal cell carcinoma (ccRCC) is a prevalent kidney cancer subtype.
- While primary ccRCC genomics are characterized, the metastatic landscape remains less understood.
Purpose of the Study:
- To comprehensively analyze the genomic alterations in metastatic ccRCC.
- To identify frequently mutated genes and copy number variations in metastatic ccRCC.
- To explore the clonal evolution and potential clinical implications of genomic changes.
Main Methods:
- Whole exome sequencing (WES) was performed on 68 ccRCC samples from 44 patients, including 52 metastatic samples.
- Analysis of somatic mutations and copy number variations (CNVs).
- Clonal evolution analysis using multi-sample data from 13 patients.
Main Results:
- SETD2, PBRM1, APC, and VHL were the most frequently mutated genes in metastatic ccRCC.
- RBM10 and FBXW7 mutations were also prevalent.
- Recurrent CNVs were observed at 3p25, 9p21, 14q25, 6p21 (CDKN1A), and 13q14 (RB1).
- Early CNVs at 3p25, 9p21, and 14q25 may correlate with rapid clinical progression.
- No significant genomic differences were found between therapy-naïve and pretreated patients.
Conclusions:
- The genomic landscape of metastatic ccRCC shares common CNVs with primary tumors.
- Mutations in RBM10, FBXW7, and CNVs at 6p21 and 13q14 warrant further investigation in metastatic ccRCC.
