CDHR5 and UPB1 expression associated with promoter methylation in sarcomatoid differentiated clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) represents the most frequent histological subtype of renal cell carcinoma (RCC). Sarcomatoid (de)differentiation is associated with metastatic dissemination and dismal prognosis. Altered DNA methylation occurs during ccRCC progression but a specific role in the emergence of sarcomatoid differentiation remains elusive. With this study, we aim to uncover DNA methylation biomarkers that might identify sarcomatoid features arising in ccRCC. In silico analyses were conducted to assess differentially methylated genes in sarcomatoid ccRCC (sccRCC) using The Cancer Genome Atlas (TCGA), looking for specific genes linked to normal cellular function, cell stemness, and metabolism. Candidate genes were then validated (promoter methylation and expression) in a tissue cohort (54 ccRCC and 34 sccRCC) using Mann-Whitney U test to compare gene methylation and transcript levels between ccRCC and sarcomatoid ccRCC groups and by plotting Receiver Operator Characteristics (ROC) with the respective biomarker performance estimated. CDHR5 me and UPB1 me levels were significantly higher in sccRCC, whereas transcript levels were significantly reduced in both independent cohorts (TCGA and our tissue cohort). Combining CDHR5 me and UPB1 me levels, sccRCC was discriminated from ccRCC with 78.7% specificity and 63% sensitivity. Furthermore, increased CDHR5 me levels significantly associated with metastatic dissemination at diagnosis in sccRCC patients. The association between epigenetic alteration of CDHR5 and UPB1 via promoter hypermethylation identifies sarcomatoid change in ccRCC and may serve as a biomarker to this end. The clinical usefulness of this finding might be increased if validated in liquid biopsies.