Renal cell carcinoma (RCC), a group of heterogeneous tumors arising from the epithelium of the renal tubules, accounts for greater than 90 % of all malignancies in the adult kidney. Classified according to the 2004 World Health Organization criteria, these tumors have unique clinical and pathological features [1]. Cytogenetic and molecular studies have also demonstrated that each histological subtype demonstrates specific genetic changes. Although different histological subtypes of RCC demonstrate unique pathogenesis and genetic alterations, the impact of histological subtypes on prognosis remains controversial [2]. In view of specific genomic and epigenetic alterations associated with a specific RCC subtype, implementation of genetic and epigenetic markers in the management of RCC might become helpful in the future.

Clear cell RCC (CCRCC) is the most common subtype, accounting for 60–75 % of RCCs. The most common and characteristic genetic change in CCRCC is an alteration of the short arm of chromosome 3 (−3p, > 90 %), followed thereafter by changes in other chromosomal regions, including 5q, 6q, 8p, 9p, 10p, and 14q [3]. Biallelic inactivation, such as by loss of one 3p arm and mutations on the second chromosome 3, is a key event in the tumor development of CCRCC. Additional chromosomal aberrations are often associated with tumor progression. At least three regions harboring several different genes on 3p have been implicated, including the von Hippel–Lindau ( VHL) gene on 3p25-26, the FHIT gene on 3p11-12, and the RASSF1Aand DRR1 genes on 3p21-22. VHL functions as a tumor suppressor and plays a critical role in the hypoxia-inducible factor (HIF) pathway. Mutations in the VHL gene lead to increased activation of the HIF pathway and its downstream target genes such as vascular endothelial growth factor ( VEGF), platelet-derived growth factor ( PGDF), epidermal growth factor ( EGF), carbonic anhydrase ( CAIX), Glut-1, and erythropoietin. These genes act in concert to promote deregulated epithelial proliferation and angiogenesis and therefore appear to contribute to the pathogenesis of CCRCC. The majority of CCRCCs are sporadic, with less than 5 % occurring in patients with inherited cancer syndromes such as von Hippel–Lindau disease, tuberous sclerosis, and constitutional chromosome 3 translocation syndrome.

Papillary RCC (PRCC) accounts for 10–15 % of RCCs. Gain of chromosomes 7 and 17 and loss of Y chromosome are the most common cytogenetic changes [4]. Additional gain of chromosomes 3, 12, 16, 20, and other chromosomes is often associated with tumor progression. The responsible genes that underlie several hereditary forms of PRCC have been identified including c-Met gene mutations (7q31) in hereditary papillary renal cell carcinoma syndrome (HPRCC) and fumarate hydratase (FH) mutations (1q42) in hereditary leiomyomatosis/renal cell carcinoma syndrome (HLRCC). Gain-of-function mutations in c-MET result in altered cellular processes related to renal papillary carcinogenesis, although these mutations are uncommon in sporadic PRCC. Fumarate hydratase functions as an enzyme that converts fumarate to malate in the tricarboxylic acid cycle. Recent studies suggest that fumarate hydratase also regulates the stability of hypoxia-inducible factors (HIFs) and may therefore play a role in renal carcinogenesis.

Chromophobe RCC (ChRCC) accounts for 5 % of RCC. It frequently has multiple complex chromosomal losses, including Y, 1, 2, 6, 10, 13, 17, and 21 [5]. Renal oncocytoma, a benign tumor that may bear morphological resemblance to chromophobe RCC, is characterized by alterations involving chromosome 11q, partial or complete losses of chromosomes 1 or 14, or a sex chromosome (Y or X). ChRCC and renal oncocytoma share some cytogenetic similarity, although the former typically demonstrates more complex karyotypic alterations than the latter. Patients with Birt–Hogg–Dube syndrome, the gene for which is mapped to 17p11.2, often develop ChRCC, oncocytoma, and hybrid tumors with features of both ChRCC and oncocytoma.

Recently, several distinct RCCs with chromosomal translocations involving the TFE3 gene at Xp11.2 and TFEB gene at 6p21 have been described [6]. The translocation results in overexpression of fusion proteins that harbor the DNA-binding domains from TFE3 and TFEB, and this overexpression has been hypothesized to function in the pathogenesis of this unique class of RCC.