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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
- Source :
- Clinical Cancer Research. 19:3259-3267
- Publication Year :
- 2013
- Publisher :
- American Association for Cancer Research (AACR), 2013.
-
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. Clin Cancer Res; 19(12); 3259–67. ©2013 AACR.
- Subjects :
- Male
Oncology
Cancer Research
medicine.medical_specialty
Tumor initiation
Biology
Bioinformatics
Article
Disease-Free Survival
Epigenesis, Genetic
PBRM1
SETD2
Internal medicine
medicine
Carcinoma
Humans
Epigenetics
Carcinoma, Renal Cell
Aged
Neoplasm Staging
Clinical Trials as Topic
BAP1
Tumor Suppressor Proteins
Nuclear Proteins
Histone-Lysine N-Methyltransferase
Middle Aged
medicine.disease
Kidney Neoplasms
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Clear cell renal cell carcinoma
Cell Transformation, Neoplastic
Mutation
Cohort
Female
Chromosomes, Human, Pair 3
Ubiquitin Thiolesterase
Transcription Factors
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....bfbe39f5e653c31aea62dc94b6affae3