Clear cell renal cell carcinoma (ccRCC) is the most common malignant renal neoplasm, comprising approximately 60 to 70 % of malignant renal tumors in adults and an advanced pathologic stage is associated with poor prognosis [1]. Understanding the molecular mechanism of carcinogenesis is important to develop more targeted therapy. ccRCC is caused by von Hippel-Lindau (VHL) gene alterations including gene mutations, loss of chromosome 3p (in particular at 3p25 locus where VHL gene is located), and gene promoter hypermethylation [2]. The VHL gene product, VHL protein, is essential to recognize and bind to hydroxylated prolyl residues on hypoxia-inducible factor (HIF), a master transcription regulator for hypoxia adaptive responses [3]. The prolyl hydroxylation is mediated by prolyl hydroxylase domain protein (PHD) enzyme in an oxygen-dependent manner [3,4]. VHL-bound HIF is degraded in the proteosome to maintain the HIF at low level when oxygen is sufficient [3]. Thus, VHL deficiency leads to an excessive HIF accumulation irrespective of oxygen concentration and overexpression of HIF targets vascular endothelial growth factors (VEGF) and erythropoietin [[3], [4], [5], [6]]. VEGF overproduction is responsible for hypervascularity of ccRCC, and an elevated erythropoietin results to polycythemia in some of ccRCC patients [3,[5], [6], [7]].

While VHL gene alterations are an initial driver of ccRCC development, additional gene abnormalities are required for further tumor progression. Such an example is chromatin remodeling genes [8,9]. Chromosome 3p harbors not only VHL gene but also crucial chromatin remodeling genes such as BAP1 (BRCA1-associated protein 1) and SETD2 (SET-domain containing 2); both genes are located at chromosome 3p21 and function as a tumor suppressor. BAP1 gene encodes a histone deubiquitinating enzyme [10,11]. BAP1 regulates gene transcription, cell cycle, DNA damage repair and cell differentiation [12]. BAP1 mutation is found in approximately 10 % of sporadic ccRCC [13,14]. BAP1-mutated ccRCC is associated with advanced tumor stage, higher tumor grade, rhabdoid and spindle morphology, and poor prognosis [[15], [16], [17]]. The detailed morphologic analysis of BAP1-mutated ccRCC is recently reported [18].

SETD2 gene encodes a trimethyltransferase enzyme that specifically methylates the histone H3 protein at Lys36 (H3K36) position [19]. H3K36 trimethylation is undetectable in cells lacking SETD2 expression [16]. SETD2 is necessary for repair of DNA double-strand breaks, thus ccRCC with SETD2 mutation displayed impaired DNA damage signaling [20]. SETD2 is mutationally inactivated in approximately 10 to 20 % of ccRCC [13,21,22]. SETD2 alteration is reported to be correlated with high-grade transformation of ccRCC [16,18]. However, in contrast to BAP1-mutated ccRCC, detail morphologic evaluation of ccRCC with SETD2 mutation is limited.

The responsible genes for high-grade ccRCC transformation are not restricted to the chromatin remodeling genes. Various other gene mutations and copy number alterations are involved, and these abnormalities often coexist [8,9]. These multiple genetic alterations obliterate the specific change caused by SETD2 mutation on tumor progression and high-grade transformation. In this study, we specifically selected ccRCC cases in which the SETD2 gene mutation was the only genetic mutation besides VHL mutation (designated herein as “SETD2-mutated ccRCC”), to investigate their histopathologic characteristics, and compare with the previously reported BAP1-mutated ccRCC [18].