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However, due to large-scale cancer genomics sequencing efforts, several driver genes beyond VHL have been
[4]
identified, and the concept of single-gene pathology underlying sporadic ccRCC has drastically evolved .
Prevalent gene mutations identified by these consortium studies included PBRM1 (40%), SETD2 (15%), and
BAP1 (10%). These tumor suppressor genes are all located on 3p21 [Figure 1] and encode for chromatin and/
[5,6]
or histone modifiers, suggesting epigenetic dysregulation as a convergent pathogenic signature in ccRCC .
Given the close genomic localization of all 4 genes spanning chromosome 3p21-25, the allelic loss of 3p is
[2]
a fundamental component of ccRCC pathogenesis [Figure 1] . These pathways by which the loss of VHL,
PBRM1, SETD2, and/or BAP1 induce disease will further be discussed in relation to function, disease
models, prognostic indications, and therapeutic advances.

THE VHL/HIF PATHWAY
VHL
VHL plays a key role in the pathogenesis of ccRCC and its inactivation has been identified as the earliest and
fundamental driving event in the development of ccRCC. The VHL tumor suppressor gene encodes for VHL,
a component of the E3 ligase complex responsible for ubiquitination of hypoxia-inducible transcription
factors 1α and 2α (HIF-1α and HIF-2α) for proteasome-mediated degradation . In a normal oxygen state,
[7,8]
HIF-1α and HIF-2α are modified by prolyl hydroxylase domain (PHD) proteins that allow VHL recognition
and binding, leading to the rapid degradation of these HIF proteins . Hypoxic conditions inactivate
[7,9]
PHD proteins that perform the posttranslational prolyl hydroxylation of HIFs for degradation, thereby
stabilizing HIF-1α and HIF-2α . Similarly, loss of VHL function by somatic mutation, hypermethylation,
[7]
or other genomic alterations of VHL, results in loss of HIF protein degradation and uninhibited HIF
activity regardless of oxygen status. Recent genomic studies have also identified a group of ccRCC tumors
[10]
that lack the characteristic 3p loss and VHL mutations but also display overexpression of HIF proteins .
These tumors are characterized by hotspot mutations in transcription elongation factor B (TCEB1), which
encodes for protein elongin C, a subunit of the Elongin (SIII) complex that plays a critical role in eukaryotic
[11]
transcription elongation . This complex is crucial for the recruitment of VHL to the VCB (VHL-elongin
C-elongin B) E3 ubiquitin ligase complex that is responsible for HIF degradation, leading to the unregulated
HIF activity. Though TCEB1-mutated RCC tumors have yet to be established as a distinct subtype,
identification of loss of TCEB1 and its effect on HIF activity supports the central HIF-driven pathogenic
theme in ccRCC tumors. Furthermore, the activation of the HIF signaling pathway is also observed in
several additional RCC subtypes, such as clear cell papillary RCC tumors which are morphologically and
[12]
clinically distinct from ccRCC .

HIF
Upon stabilization, HIF-1α accumulates and directly regulates cellular metabolism in coping with the low
oxygen environmental stress. Additionally, HIF-1α, like HIF-2α, dimerizes with HIF-1β or aryl hydrocarbon
receptor nuclear translocator, producing an active transcription factor. HIF-1 and HIF-2 dimer complexes
then activate and upregulate the transcription of numerous hypoxia-inducible targets genes, many of which
[7]
mediate cell metabolism and growth . These target genes differ among different cell lines and tissues, and
[13]
the sets of genes regulated by HIF-1α and HIF-2α, respectively, overlap but are not identical . In kidney
cells, glycolysis is primarily driven by HIF-1α, whereas HIF-2α regulates expression of vascular endothelial
[14]
growth factor A (VEGFA), cyclin D1, erythropoietin, and C-X-C chemokine receptor 4 .

[15]
Increased HIF-1α levels have been associated with increased mortality in many types of human cancers .
However, the role of HIF-1 and HIF-2 in ccRCC has not yet been fully elucidated, as they seem to both affect
the development and progression of ccRCC. Mouse models with constitutive HIF-1α, not HIF-2α, expression
in the renal proximal tubule developed ccRCC [16,17] . Elimination of HIF-2α in VHL-/- ccRCC xenograft
assays can suppress their ability to form tumors in nude mouse, while HIF-2α overproduction can override
intact VHL tumor suppressor function [14,18,19] . Furthermore, HIF-2α single nucleotide polymorphisms have