The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma).A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival.Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.

Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 (Kelch-like erythroid-derived cap-n-collar homology- (ECH-) associated protein-1/nuclear factor (erythroid-derived 2)-like 2) axis. The physical interaction between these two proteins promotes the expression of several antioxidant defense genes in response to exogenous and endogenous insults. Recent studies demonstrated that KEAP1/NRF2 axis dysfunction is also strongly related to tumor progression and chemo- and radiotherapy resistance of cancer cells. In solid tumors, the KEAP1/NRF2 system is constitutively activated by the loss of KEAP1 or gain of NFE2L2 functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes. In addition to point mutations, epigenetic abnormalities, as aberrant promoter methylation, and microRNA (miRNA) and long noncoding RNA (lncRNA) deregulation were reported as emerging mechanisms of KEAP1/NRF2 axis modulation. This review will summarize the current knowledge about the epigenetic mechanisms that deregulate the KEAP1/NRF2 cascade in solid tumors and their potential usefulness as prognostic and predictive molecular markers.

The programmed death 1 receptor (PD-1) and its ligand (PD-L1) are key molecules of immune checkpoint mechanisms in cancer and actually represent one of the main targets of immunotherapy. The predictive and prognostic values of PD-L1 expression alone in cancer patients is currently under debate due to the methodological assessment of PD-L1 expression and its temporal variations. Better detailed studies about the molecular basis of immunotherapy biomarkers are necessary. Here we summarize the current knowledge of PD-L1 gene modifications at genetic and epigenetic levels in different tumors, thus highlighting their reported correlation with cellular processes and potential impact on patient outcomes.