Pathogenic Germline Mutational Landscape in Patients With Renal Cell Carcinoma and Associated Clinicopathologic Features

A subset of renal cell carcinoma (RCC) cases occur because of a hereditary predisposition. However, the prevalence and profiling of germline alterations in RCC have not been fully characterized. Additionally, clinicopathologic factors associated with pathogenic or likely pathogenic (P/LP) germline variants in patients with RCC remain poorly understood.A retrospective analysis of patients with RCC who underwent genetic evaluation was performed. The frequency of P/LP germline variants and genes was evaluated in this cohort. The association between genetic testing outcomes and clinicopathologic features was also assessed.A total of 321 patients with RCC who had germline testing were identified. Within this cohort, 42 patients (13.1%) had P/LP variants. Genes with the most frequent germline mutations were FLCN (n = 10, 3.1%), SDHB (n = 4, 1.2%), VHL (n = 4, 1.2%), MLH1 (n = 3, 0.9%), and CHEK2 (n = 4, 1.2%). Among patients with P/LP variants, 19 (45.2%) had a potentially targetable mutation. The presence of bilateral or multifocal tumors was associated with P/LP variants (P = .0012 and P = .0098, respectively). Patients who had targeted gene testing had higher rates of P/LP variants compared with multigene panel testing (P = .015). Age and family history of cancers (RCC and non-RCC) did not have any statistically significant association with germline testing outcomes.Among patients with RCC, unselected for a known familial predisposition, 13.4% had P/LP variants. Almost half of patients with P/LP variants had a potentially targetable mutation. Targeted gene panel testing is a feasible option for patients, particularly if syndromic features are present. Age and family history were not associated with P/LP variants. Future studies are needed to optimize current genetic evaluation criteria to expand the detection of patients with RCC who may have germline mutations.