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.

Surgery: Urology Service, Memorial Sloan Kettering Cancer Center.
Clinical Cancer Research (Impact Factor: 8.19). 04/2013; 19(12). DOI: 10.1158/1078-0432.CCR-12-3886
Source: PubMed

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 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts. Patients and Methods Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was performed to interrogate the genotype-phenotype associations. These findings were compared to analyses of the genomic and clinical dataset from our non-overlapping The Cancer Genome Atlas (TCGA) cohort of 421 primary ccRCC patients. 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 (2.08-28.6); TCGA, p=0.002, HR 2.21 (1.35-3.63)). SETD2 are associated with worse CSS in the TCGA cohort (p=0.036, HR 1.68 (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 three 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.

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