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Le et al. J Transl Genet Genom 2018;2:17. I https://doi.org/10.20517/jtgg.2018.28 Page 5 of 9

In particular to integrate mechanistic and therapeutic research completed on these pathways, we propose a
model depicting the interconnection of VHL-HIF-PBRM1-TSC-mTORC1 in the development in ccRCC. This
model involves three inactivating steps: (1) VHL loss; (2) VHL-PBRM1 loss; (3) VHL-PBRM1-TSC loss. The
initial complete pathologic loss of VHL via chromosome 3p loss, mutations, and/or promoter methylation
results in pseudohypoxia - a hypoxia-like molecular response despite normoxic conditions due to aberrant
accumulation of HIF proteins. As observed in both human and mouse VHL loss models, the loss of VHL
[44]
is insufficient in initiating ccRCC development . The subsequent loss of PBRM1 signifies the second step
HIF-PBRM1-STAT, which leads to a dysregulated feed-forward amplification loop of maximal downstream
[30]
gene expression . As evidenced by the PBRM1-/- VHL-/- mouse model, the activation of mTORC1 either
by loss of TSC suppression or by aberrant increase in mTORC1 activity may encompass the third oncogenic
[30]
step in ccRCC .

SETD2
SETD2 mutations are observed in 10% of human ccRCC primary tumors, and the frequency dramatically
increase to ~30% in metastatic ccRCC patient samples , thereby representing an important molecular
[40]
aberration in ccRCC metastatic progression [27,45] . SETD2 encodes a histone H3 lysine 36 methyltransferases
[46]
that utilize a conserved SET domain . Most significantly, SETD2-gene products are responsible for
the trimethylation of the histone H3K36, loss of which is associated with widespread RNA processing
defects, thereby affecting chromatin accessibility, transcriptional activation, DNA repair, and cell cycle
[48]
[47]
regulation . SETD2 functions as a tumor suppressor in several types of cancer, including breast cancer
and leukemia , and post-transcriptional regulation of SETD2 may be correlated with tumor development
[49]
[50]
in breast cancer and ccRCC ; additionally, several studies suggest inactivating mutations of SETD2 occur
most prevalently in ccRCC and non-small cell lung cancer [26,51] .
SETD2 mutations are clinically associated with worse kidney cancer specific survival [27,52] and ccRCC
[40]
metastasis , though SETD2 loss is not correlated with poor targeted treatment outcomes [40,53] . Tumor
associated SETD2 mutations also highlight the presence of significant intratumor heterogeneity in ccRCC [1,54] .
Multiple SETD2 mutation variants have been identified among different tumor regions in individual
patients, suggesting its role in the convergent evolution of ccRCC [6,39] . Given its frequency of inactivation in
ccRCC and its critical role as a tumor suppressor, loss of SETD2 function represents an important genomic
progression marker in ccRCC.

BAP1
BAP1, like SETD2 and PBRM1, is found on chromosome 3p21. BAP1 encodes for a deubiquitinating enzyme,
shown to bind breast cancer type 1 susceptibility protein (BRCA1) and BRCA1-associated RING domain
protein 1 (BARD1) and thereby function as a tumor suppressor by inhibiting the ability of BRCA1/BARD1 to
mediate ubiquitination and autoubiquitination [55,56] . BAP1 also regulates transcription via histone modulation,
thus playing a key role in cell cycle and growth, cellular response to DNA damage, and chromatin
[57]
dynamics . BAP1 mutations are prevalent in about 10% of human ccRCC cases, and loss of BAP1 function is
associated with tumors of high grade and large size as well as poor overall clinical outcome despite targeted
therapy [27,28,40] . Kidney-specific homozygous deletion of VHL and BAP1 in mice resulted in early death,
though some mice with heterozygous deletion of BAP1 and complete loss of VHL developed tumors only
[58]
moderately resembling human ccRCC . Further preclinical investigation of the BAP1 interaction with VHL
inactivation is required to more clearly define the role of BAP1 in ccRCC tumorigenesis.

CURRENT AND EMERGING THERAPEUTICS
The management of metastatic ccRCC has improved dramatically over the last decade [Figure 2]. Prior to
2005, only two drugs were approved for the medical treatment of advanced ccRCC and the median survival
[1]
was poor (15 months) . The introduction of targeted therapies expanded the treatment options greatly and