Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma Journal Article

Authors: Hakimi, A. A.; Chen, Y. B.; Wren, J.; Gonen, M.; Abdel-Wahab, O.; Heguy, A.; Liu, H.; Takeda, S.; Tickoo, S. K.; Reuter, V. E.; Voss, M. H.; Motzer, R. J.; Coleman, J. A.; Cheng, E. H.; Russo, P.; Hsieh, J. J.
Article Title: Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma
Abstract: Background: Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. Objective: To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. Design, setting, and participants: Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. Outcome measurements and statistical analysis: The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). Results and limitations: PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events. Conclusions: Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted. © 2012 European Association of Urology.
Keywords: adult; controlled study; human tissue; aged; middle aged; unclassified drug; gene mutation; gene sequence; major clinical study; mutation; cancer staging; follow up; neoplasm staging; cytoreductive surgery; phenotype; gene targeting; genetic predisposition to disease; gene frequency; odds ratio; risk factors; renal cell carcinoma; kidney carcinoma; kidney neoplasms; time factors; risk assessment; gene expression regulation, neoplastic; carcinoma, renal cell; tumor burden; histone; chromatin; cancer specific survival; outcome; dna mutational analysis; tumor suppressor protein; fisher exact test; genes, tumor suppressor; genetic linkage; chromatin assembly and disassembly; log rank test; kaplan-meier estimate; setd2 protein; neoplasm grading; bap1 protein; kdm5c protein; pbrm1 protein
Journal Title: European Urology
Volume: 63
Issue: 5
ISSN: 0302-2838
Publisher: Elsevier Science, Inc.  
Date Published: 2013-05-01
Start Page: 848
End Page: 854
Language: English
PROVIDER: scopus
PMCID: PMC3615105
PUBMED: 23036577
DOI: 10.1016/j.eururo.2012.09.005
Notes: --- - Cited By (since 1996):2 - "Export Date: 1 May 2013" - "CODEN: EUURA" - ":doi 10.1016/j.eururo.2012.09.005" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jonathan Coleman
    184 Coleman
  2. Adriana Heguy
    85 Heguy
  3. Paul Russo
    446 Russo
  4. Robert Motzer
    744 Motzer
  5. Mithat Gonen
    701 Gonen
  6. Satish K Tickoo
    369 Tickoo
  7. Martin Henner Voss
    126 Voss
  8. Yingbei Chen
    221 Chen
  9. Shugaku Takeda
    16 Takeda
  10. James J Hsieh
    114 Hsieh
  11. Han Liu
    12 Liu
  12. Emily H Cheng
    55 Cheng
  13. Victor Reuter
    899 Reuter
  14. James Wren
    5 Wren
  15. Abraham Ari Hakimi
    129 Hakimi