360 Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p<0.0001 HR 4.03 [2.1-7.9]). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusions: BAP1, SETD2 and KDM5C mutations are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations 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.
Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma