Saleeb RM, Farag M, Ding Q, et al. - A total of 140 papillary adenomas (PAs, a small benign lesion morphologically comparable to PRCC and is recommended to be its precursor), normal kidneys, end-stage kidney diseases (ESKDs), and papillary renal cell carcinomas (PRCCs) were investigated to determine the evolution of PAs to PRCCs and their relation to ESKD. Compared with the normal kidney, in ESKD and PAs, progenitor cells were significantly raised. Pathway analysis using global miRNA and chromosomal copy number variations exhibited a familiar developmental theme between PA and the PRCCs. Among all PAs and PRCCs, whole-exome sequencing explicated a KMT2C-specific pathogenic mutation. KMT2C is a chromosome 7 epigenetic regulator involved in development and oncogenesis. Altogether, a potential association of PRCCs to PA and the progenitor-like cell population, which are raised in response to renal tubular injury, was demonstrated. Moreover, each PRCC histologic subtype had its own set of mutational alterations, symbolizing deviation from a prevalent precursor. The study describes formerly unknown biological perspectives of PRCC development and could impact prevailing surveillance criteria and early discovery approaches of PRCC tumors.