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Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma
Carolin Sauter-Meyerhoff1, Regina Bohnert1, Pascale Mazzola1
1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
Abstract:
Metastatic renal cell carcinoma (RCC) exhibits poor prognosis. Better knowledge of distant metastases is crucial to foster personalized treatment strategies. Here, we aimed to investigate the genetic landscape of metastases, including synchronous and/or recurrent metastases to elucidate potential drug target genes and clinically relevant mutations in a real-world setting of patients. We assessed 81 metastases from 56 RCC patients, including synchronous and/or recurrent metastases of 19 patients. Samples were analysed through next-generation sequencing with a high coverage (~1000× mean coverage). We therefore established a novel sequencing panel comprising 32 genes with impact on RCC development. We observed a high frequency of mutations in known RCC driver genes (e.g., >40% carriers of VHL and PBRM1 mutations) in metastases irrespective of the metastatic site. The somatic mutational composition was significantly associated with cancer-specific survival (p(logrank) = 0.03). Moreover, we identified in 34 patients at least one drug target gene as well as clinically relevant mutations listed in the VICC Meta-Knowledgebase in 7%. In addition to significantly higher mutational burden in recurrent metastases compared to earlier ones, synchronous and/or recurrent metastases of individual patients, even after a time-period >2 yrs, shared a high proportion of somatic events. Our data demonstrate the importance of somatic profiling in metastases for precision medicine in RCC.
Insights
Investigating the genetic makeup of metastatic renal cell carcinoma (RCC) reveals key mutations in driver genes. This somatic profiling of metastases is vital for developing targeted therapies and improving patient outcomes in advanced RCC.
Area of Science:
- Oncology
- Genetics
- Precision Medicine
Background:
- Metastatic renal cell carcinoma (RCC) presents a significant clinical challenge with poor patient prognosis.
- Understanding the genetic alterations in distant metastases is essential for tailoring personalized treatment strategies.
- Previous research has focused on primary tumors, leaving the genetic landscape of metastases underexplored.
Purpose of the Study:
- To investigate the genetic profile of metastatic renal cell carcinoma (RCC) lesions, including synchronous and recurrent metastases.
- To identify potential drug target genes and clinically relevant mutations within these metastases.
- To correlate the genetic landscape of metastases with patient survival outcomes in a real-world setting.
Main Methods:
- Analysis of 81 metastases from 56 RCC patients using next-generation sequencing with a novel 32-gene panel.
- High-coverage sequencing (~1000× mean coverage) was employed for comprehensive genetic assessment.
- Inclusion of synchronous and/or recurrent metastases from 19 patients to capture disease heterogeneity.
Main Results:
- High frequencies of mutations in known RCC driver genes (e.g., VHL, PBRM1) were observed across all metastatic sites.
- Somatic mutational composition showed a significant association with cancer-specific survival (p=0.03).
- Drug targetable mutations or VICC Meta-Knowledgebase-listed mutations were identified in 7% of patients; recurrent metastases exhibited higher mutational burden.
Conclusions:
- Somatic profiling of metastases provides critical insights into the genetic drivers of advanced renal cell carcinoma.
- The genetic landscape of metastases is associated with patient survival, supporting its clinical relevance.
- Synchronous and recurrent metastases share a significant proportion of somatic events, underscoring the need for metastasis-directed molecular analysis in precision oncology.
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