What genetic mutations and syndromes are associated with Papillary Renal Cell Carcinoma (PRCC)?

From the Guidelines

Papillary renal cell carcinoma (PRCC) is associated with several genetic mutations and syndromes, including mutations in the MET gene, particularly in type 1 PRCC, and mutations in the FH gene, which is linked to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. The most significant genetic alterations in PRCC include:

• Mutations in the MET gene, particularly in type 1 PRCC, as reported in 1
• Mutations in the FH gene, which is linked to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, as mentioned in 1
• Alterations in the NRF2-antioxidant response element pathway, as discussed in 1
• Mutations in genes such as CDKN2A, SETD2, and BAP1, as noted in 1 Hereditary papillary renal cell carcinoma (HPRCC) is an autosomal dominant syndrome caused by activating mutations in the MET proto-oncogene, predisposing affected individuals to develop multiple, bilateral papillary renal tumors, as described in 1. Birt-Hogg-Dubé syndrome, caused by mutations in the FLCN gene, can also present with papillary renal tumors alongside other manifestations, as mentioned in 1. These genetic alterations drive tumor development by affecting cellular pathways involved in metabolism, proliferation, and response to hypoxia, as discussed in 1. Understanding these genetic underpinnings is crucial for accurate diagnosis, risk assessment in family members, and development of targeted therapies for patients with PRCC, as emphasized in 1. Key points to consider in the diagnosis and management of PRCC include:
• The recognition of new RCC subtypes, many demonstrating at least focal papillary architecture, as reported in 1
• The importance of excluding other entities that may show papillary architecture, such as FH-deficient RCC, MITF family translocation family RCC, renal medullary carcinoma, collecting duct carcinoma, and acquired cystic disease-associated RCC, as noted in 1
• The use of molecular classification to stratify PRCC into biologic subtypes, as proposed in 1
• The consideration of tumor architecture, including specific morphologic patterns, in predicting outcome, as discussed in 1

From the Research

Genetic Mutations and Syndromes Associated with Papillary Renal Cell Carcinoma

• Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene 2, 3.
• The MET gene is commonly altered in type 1 PRCC, while multiple alterations are involved in type 2 PRCC 4.
• Activating mutations of MET were present in three cell lines that all demonstrated increased MET phosphorylation in response to HGF and abrogation of MET phosphorylation in response to MET inhibitors 5.
• Type 1 PRCC tends to have more alterations in the MET tyrosine kinase receptor than Type 2 PRCC 6.

Syndromes Associated with Papillary Renal Cell Carcinoma

• Hereditary papillary renal cell carcinoma (HPRCC) syndrome is an autosomal dominant syndrome characterized by the occurrence of bilateral and multifocal, classic type papillary renal cell carcinomas 3.
• HPRCC syndrome is associated with missense mutations in the tyrosine kinase domain of the MET proto-oncogene 3.
• The presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study 2.