Genomic profiling in renal cell carcinoma

• Published in: Nature reviews. Nephrology 2020-08, Vol.16 (8), p.435-451
• Main Authors: Dizman, Nazli, Philip, Errol J., Pal, Sumanta K.
• Format: Article
• Language: English
• Subjects: 631/208/212/2166; 692/4022/1585/1588/1351; 692/53/2422; 692/699/67/1059/602; Angiogenesis Inhibitors - therapeutic use; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Immunological - therapeutic use; Carcinoma, Renal cell; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Care and treatment; Clinical outcomes; Development and progression; DNA methylation; DNA Methylation - genetics; DNA Repair - genetics; DNA-Binding Proteins - genetics; Enhancer of Zeste Homolog 2 Protein - genetics; Gene mutations; Genetic aspects; Genomics; Health aspects; Histone-Lysine N-Methyltransferase - genetics; Humans; Identification and classification; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Medicine; Medicine & Public Health; Molecular Targeted Therapy; Mutation; Nephrology; Neurofibromin 2 - genetics; Precision Medicine; Prognosis; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-met - genetics; PTEN Phosphohydrolase - genetics; Review Article; Telomerase - genetics; Transcription Factors - genetics; Transcriptome; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - genetics; Ubiquitin Thiolesterase - genetics; Von Hippel-Lindau Tumor Suppressor Protein - genetics
• ISSN: 1759-5061; 1759-507X
• DOI: 10.1038/s41581-020-0301-x

The treatment landscape of metastatic renal cell carcinoma (RCC) has been revolutionized over the past two decades, bringing forth an era in which more than a dozen therapeutic agents are now available to treat patients. As a consequence, personalized care has become a critical part of developing effective treatment guidelines and improving patient outcomes. One of the most important emerging aspects of precision medicine in cancer is matching patients and treatments based on the genomic characteristics of an individual and their tumour. Despite the lack of a single genomic predictor of treatment response or prognostication feature in RCC, emerging research suggests that the identification of such markers remains promising. Mutations in VHL and alterations in its downstream pathways are the mainstay of RCC development and progression. However, the predictive value of VHL mutations has been questioned. Further research has examined mutations in genes involved in chromosome remodelling (for example, PBRM1 , BAP1 and SETD2 ), DNA methylation and DNA damage repair, all of which have been associated with clinical outcomes. Here, we provide a comprehensive overview of genomic evidence in the context of RCC and its potential predictive and prognostic value. Genomic profiling of renal cell carcinoma has demonstrated the clinical relevance of several genetic alterations in different disease subtypes. Pal and colleagues discuss the prognostic and predictive value of these alterations, and how they might help to improve treatment selection and patient outcomes. Key points Renal cell carcinoma (RCC) is a complex disease entity with different histological subtypes characterized by distinct clinical and pathophysiological features; genomic research has identified relevant alterations associated with each RCC subtype. In the past two decades, new insights into the mechanisms that underlie the development and progression of RCC have expanded treatment options; genomic data might guide treatment choices by enabling individuals to be matched with therapeutics that specifically target the genomic and molecular alterations present in their tumours. Despite a mechanistic link between VHL alterations and RCC, alterations in this driver gene are not clearly associated with clinical outcomes. Growing evidence supports the prognostic value of chromatin remodelling genes, such as PBRM1 and BAP1 ; alterations in PBRM1 also seem to have predictive value in responses to immunotherapy.