Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma

SIMPLE SUMMARY: Survival rates in metastatic renal cell carcinoma (RCC) are still low despite novel therapies available. Thus, knowledge of molecular characteristics of distant metastases is important for personalized treatment strategies. Therefore, we investigated the genetic landscape of metastases, including synchronous and/or recurrent metastases to elucidate potential drug target genes and clinically relevant mutations. Furthermore, differences in mutational composition in different metastatic sites and over the course of the disease and treatment will demonstrate the importance of somatic profiling for precision medicine in RCC, thereby improving disease management in the future. 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.