Integration of recurrent somatic mutations with clinical outcomes: A pooled analysis of 1049 patients with clear cell renal cell carcinoma Journal Article


Authors: Manley, B. J.; Zabor, E. C.; Casuscelli, J.; Tennenbaum, D. M.; Redzematovic, A.; Becerra, M. F.; Benfante, N.; Sato, Y.; Morikawa, T.; Kume, H.; Fukayama, M.; Homma, Y.; Ogawa, S.; Arcila, M. E.; Voss, M. H.; Feldman, D. R.; Coleman, J. A.; Reuter, V. E.; Motzer, R. J.; Russo, P.; Hsieh, J. J.; Hakimi, A. A.
Article Title: Integration of recurrent somatic mutations with clinical outcomes: A pooled analysis of 1049 patients with clear cell renal cell carcinoma
Abstract: 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. © 2016 European Association of Urology
Keywords: adult; controlled study; aged; major clinical study; somatic mutation; mutation; clinical feature; mortality; cancer staging; tumor volume; genetic association; mutational analysis; protein p53; renal cell carcinoma; oncogene; dna; cancer specific survival; scoring system; dna sequence; recurrence free survival; bap1 gene; tp53 gene; prognosis; human; male; female; article; sequencing analysis
Journal Title: European Urology Focus
Volume: 3
Issue: 4-5
ISSN: 2405-4569
Publisher: European Association of Urology  
Date Published: 2017-10-01
Start Page: 421
End Page: 427
Language: English
DOI: 10.1016/j.euf.2016.06.015
PROVIDER: scopus
PMCID: PMC5650556
PUBMED: 28753773
DOI/URL:
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Jonathan Coleman
    181 Coleman
  2. Paul Russo
    443 Russo
  3. Robert Motzer
    707 Motzer
  4. Darren Richard Feldman
    164 Feldman
  5. Martin Henner Voss
    122 Voss
  6. Emily Craig Zabor
    119 Zabor
  7. James J Hsieh
    114 Hsieh
  8. Maria Eugenia Arcila
    328 Arcila
  9. Victor Reuter
    890 Reuter
  10. Abraham Ari Hakimi
    127 Hakimi
  11. Brandon John Manley
    21 Manley
  12. Maria Fernanda   Becerra
    15 Becerra