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.

TitleAdverse 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.
Publication TypeJournal Article
Year of Publication2013
AuthorsA Hakimi, A, Ostrovnaya, I, Reva, B, Schultz, N, Chen, Y-B, Gonen, M, Liu, H, Takeda, S, Voss, MH, Tickoo, SK, Reuter, VE, Russo, P, Cheng, EH, Sander, C, Motzer, RJ, Hsieh, JJ
Corporate AuthorsccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators
JournalClin Cancer Res
Volume19
Issue12
Pagination3259-67
Date Published2013 Jun 15
ISSN1078-0432
KeywordsAged, Carcinoma, Renal Cell, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 3, Clinical Trials as Topic, Disease-Free Survival, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase, Humans, Kidney Neoplasms, Male, Middle Aged, Mutation, Neoplasm Staging, Nuclear Proteins, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase
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; HR 1.68; 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.

DOI10.1158/1078-0432.CCR-12-3886
Alternate JournalClin. Cancer Res.
PubMed ID23620406
PubMed Central IDPMC3708609
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
T32 CA009207 / CA / NCI NIH HHS / United States
T32 CA082088 / CA / NCI NIH HHS / United States
T32 CA082088 / CA / NCI NIH HHS / United States
U24 CA143840 / CA / NCI NIH HHS / United States
U24CA143840 / CA / NCI NIH HHS / United States