Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: A report by MSKCC and the KIRC TCGA research network Journal Article


Authors: Hakimi, A. A.; Ostrovnaya, I.; Reva, B.; Schultz, N.; Chen, Y. B.; Gonen, M.; Liu, H.; Takeda, S.; Voss, M. H.; Tickoo, S. K.; Reuter, V. E.; Russo, P.; Cheng, E. H.; Sander, C.; Motzer, R. J.; Hsieh, J. J.; for The ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators
Article Title: Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: A report by MSKCC and the KIRC TCGA research network
Abstract: Purpose: To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer-specific survival (CSS) of 609 patients with clear cell renal cell carcinoma (ccRCC) from 2 distinct cohorts. Experimental Design: Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was conducted to interrogate the genotype-phenotype associations. These findings were compared with analyses of the genomic and clinical dataset from our nonoverlapping The Cancer Genome Atlas (TCGA) cohort of 421 patients with primary ccRCC. Results: 3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts [MSKCC, P = 0.002; HR 7.71; 95% confidence interval (CI) 2.08-28.6; TCGA, P = 0.002; HR 2.21; 95% CI 1.35-3.63]. SETD2 are associated with worse CSS in the TCGA cohort (P = 0.036; HR1.68; 95%CI 1.04-2.73). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusion: The chromosome 3p21 locus harbors 3 frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6%-12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30%-34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic, and molecular interrogation of this novel class of tumor suppressors. © 2013 American Association for Cancer Research.
Keywords: adult; controlled study; human tissue; aged; gene mutation; gene sequence; major clinical study; overall survival; missense mutation; cancer growth; cohort analysis; gene locus; genetic association; mutational analysis; wild type; kidney carcinoma; nephrectomy; tumor suppressor gene; cancer specific survival; chromosome 3p; mutant; genotype phenotype correlation; bap1 gene; pbrm1 gene; setd2 gene
Journal Title: Clinical Cancer Research
Volume: 19
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2013-06-15
Start Page: 3259
End Page: 3267
Language: English
DOI: 10.1158/1078-0432.ccr-12-3886
PROVIDER: scopus
PMCID: PMC3708609
PUBMED: 23620406
DOI/URL:
Notes: --- - Cited By (since 1996):1 - "Export Date: 1 August 2013" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Paul Russo
    582 Russo
  2. Robert Motzer
    1248 Motzer
  3. Mithat Gonen
    1033 Gonen
  4. Satish K Tickoo
    486 Tickoo
  5. Martin Henner Voss
    294 Voss
  6. Yingbei Chen
    401 Chen
  7. Shugaku Takeda
    18 Takeda
  8. Boris A Reva
    36 Reva
  9. James J Hsieh
    125 Hsieh
  10. Han Liu
    13 Liu
  11. Emily H Cheng
    78 Cheng
  12. Chris Sander
    210 Sander
  13. Victor Reuter
    1231 Reuter
  14. Nikolaus D Schultz
    491 Schultz
  15. Abraham Ari Hakimi
    327 Hakimi