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

Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts.

To define clinicopathologic associations between specific mutations and ccRCC disease characteristics.

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.

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.

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.

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.

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.

European urology focus. 2016 Jul 16 [Epub ahead of print]

Brandon John Manley, Emily C Zabor, Jozefina Casuscelli, Daniel M Tennenbaum, Almedina Redzematovic, Maria F Becerra, Nicole Benfante, Yusuke Sato, Teppei Morikawa, Haruki Kume, Masashi Fukayama, Yukio Homma, Seishi Ogawa, Maria E Arcila, Martin H Voss, Darren R Feldman, Jonathan A Coleman, Victor E Reuter, Robert J Motzer, Paul Russo, James J Hsieh, A Ari Hakimi

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: .