Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma

Background: Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. Objective: To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. Design, setting, and participants: DNA sequencing data were pooled from three collaborative genomic cohorts (n = 754) and our institutional database (n = 295). All patients had clinical data and identification of somatic mutations from their primary tumors. Outcome measurements and statistical analysis: Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing (q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. Results and limitations: Association with tumor size was found for mutations in BAP1 (q = 0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 (q = 0.004) and TP53 (q = 0.001) were associated with decreased CSS in a multivariable model; only TP53 (q = 0.005) remained significant when SSIGN score was included. SETD2 mutations (q = 0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. Conclusions: In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53. After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. Patient summary: Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence. In this study of >1000 patients with clear cell renal cell carcinoma, pooled analysis and multivariable modeling demonstrated that three recurrently mutated genes, BAP1, SETD2, and TP53, have statistically significant associations with poor clinical outcomes.