Kidney cancer is one of the 15 most
common malignancies occurring globally, with more than 270,000 new cases every
year worldwide (1-3). The majority of malignant kidney tumors are renal cell
carcinomas (RCC) with the most common and aggressive subtype being clear-cell
renal cell carcinoma (ccRCC), comprising approximately 70% of all kidney tumors
(4). Localized ccRCC is potentially curable by resection, though about 30% of
patients relapse after initial nephrectomy (5). Unfortunately, ccRCC is
frequently non-symptomatic in the early phases, and is repeatedly detected in
advanced stage often with metastases (6). When metastasized, ccRCC is chemo-
and radiation-resistant and in most cases remains incurable, resulting in a 95%
mortality rate (7, 8).
To date no effective ccRCC treatment
has been developed and none of the potential biomarkers have been approved for
clinical application. For many years von Hippel-Lindau (VHL) tumor suppressor
gene (TSG) was the only TSG associated with ccRCC pathogenesis (9). Attempts to
detect other mutated genes have been unsuccessful for a long time, though
deregulation of chromatin machinery has recently emerged as an important
mechanism in renal neoplasms. Large-scale sequencing projects have identified
novel TSGs, mapped to the frequently lost 3p21 locus and functioning as
epigenetic chromatin and/or histone modifiers, indicating epigenetic changes
may play an important role in ccRCC development (10-12). Silencing of VHL
through promoter methylation in ccRCC was one of the first examples of this
phenomenon and so far approximately 60 genes have been suggested to be
epigenetically deregulated in ccRCC (13). Here, we summarize the most recent
discoveries in the field of ccRCC epigenomics, providing potential diagnostic
and prognostic biomarkers as well as possible novel targets for therapeutic
intervention.
Epigenetic alterations in ccRCC
The main mechanisms responsible for
chromatin state regulation are: DNA methylation, nucleosome remodeling, and
covalent histone modifications through methylation, acetylation,
phosphorylation, ubiquitination, or sumoylation. These modifications can
directly change DNA organization and/or accessibility as well as lead to the
recruitment of proteins altering chromatin structure and in consequence influence
transcription, replication, recombination and DNA repair (14, 15). Recent
genome-wide methylation studies and sequencing projects demonstrated that the
disruption of epigenetic control has a significant role in the initiation and
progression of ccRCC (16-18).
Inactivation of potential tumor suppressor genes
through DNA methylation
DNA methylation is the best studied
epigenetic modification and the only epigenetic mark with a well described mechanism
of mitotic inheritance (19). It plays an important role in various biological
processes, for example, genomic imprinting, transposable elements silencing,
and embryonic development (20). Methylation patterns are generated and
maintained by DNA methyltransferases (DNMTs). DNMT1 acts during replication and
maintains methylation of the new DNA strand, DNMT3a and DNMT3b are de novo
methyltransferases that act independently of replication and display no preference
for unmethylated nor hemi-methylated DNA (20-23).
The majority of CpG-rich promoter
regions (CpG islands) occupying near 60% of human gene promoters usually remain
unmethylated (24). Gene silencing by promoter region methylation of TSGs is a
frequent mechanism described in human cancers, with epigenetic inactivation of
VHL in ccRCC being one of the first examples (13, 25, 26). VHL, while mutated
in approximately 80% of sporadic ccRCC, is inactivated by methylation in an
additional ~10% of cases (27, 28). Identification of other epigenetically inactivated
TSGs was an important approach to study the pathogenesis of ccRCC, and promoter
hypermethylation of several genes commonly inactivated in ccRCC has been
documented (18). Based on a search of online databases, compilation of
candidate genes reported in numerous studies to show tumor-specific
hypermethylation in ccRCC, has been published in 2010 (28). Morris et al.
described 38 genes methylated in ccRCC, among those only a small number was
methylated with high frequency (≥50% of cases: APAF1, COL1A1, DKK2, DKK3,
SFRP2, SFRP4, SFRP5, and WIF1) while rarely (<10%) in matched normal tissue
(28).
The earlier, initial studies mostly
implemented targeted, candidate-driven analyses. Recently, several whole genome
strategies also have been applied. A large functional epigenetic screen of gene
upregulation post 5-aza-2’-deoxycytidine demethylation treatment by
high-density gene expression microarrays in 11 RCC cell lines (KTCL 26, RCC4,
UMRC2, UMRC3, SKRC18, SKRC39, SKRC45, SKRC47, SKRC54, 786-0 and Caki-1) was
applied by Morris et al. Genes
re-expressed after demethylation were validated in 61 primary tumors (~80%
clear cell and 20% non-clear cell RCC). Five genes (BNC1, COL14A1, CST6,
PDLIM4, and SFRP1) demonstrated frequent tumor-specific promoter region methylation
(>30%), associated with transcriptional silencing. Re-expression of BNC1,
CST6, and SFRP1 suppressed the growth of RCC cell lines, whereas RNAi
knock-down of BNC1, SFRP1, and COL14A1 increased their growth, suggesting tumor
suppressor activity (29). Similarly, methylated DNA immunoprecipitation (MeDIP)
of primary tumors, followed by high-density whole-genome expression microarray
comparative analysis revealed 9 genes frequently methylated in primary ccRCC
tumour samples: PCDH8 (58%), KLHL35 (39%), ATP5G2 (36%), CCDC8 (35%), FBN2
(34%), ZSCAN18 (32%), their promoter hypermethylation resulting in gene
silencing (30). None of these genes have been reported previously to be
methylated in RCC nor other cancers.
Genome-wide DNA methylation studies in ccRCC
have also been performed using BeadChip arrays. Comparison of DNA methylation profiles in familial (n = 29)
and sporadic (n = 20) VHL+/+ ccRCC showed more frequently methylated
RASSF1, PITX2, CDH13, HS3ST2, TWIST1, TAL1, TUSC3, and DCC loci in sporadic
cases, indicating differences in tumorigenesis mechanisms dependent on VHL
status (31). Several novel ccRCC TSG candidates (SLC34A2, OVOL1, DLEC1,
TMPRSS2, SSTand BMP4) have been found in a global study of CpG methylation in
38 ccRCC and 9 age-matched healthy tissues (~27,500 CpGs and >14,000 genes)
(32). All of those exhibited frequent transcriptional silencing associated with
promoter methylation (20-60% of cases).
Dmitriev et al. focused on genetic and epigenetic destabilization of genes
on chromosome 3 (33). The study (validated by bisulfite genomic sequencing)
showed 22 genes displaying high frequency of methylation (17–57%) and/or
deletion in ccRCC. Identified genes included well-known TSGs VHL, CTDSPL,
LRRC3B, ALDH1L1, and EPHB1, but also genes not previously linked to cancer
development (LRRN1, GORASP1, FGD5, and PLCL2). Proteins encoded by a part of
these genes are involved in signaling pathways and biological processes
frequently affected in cancer, like apoptosis (GORASP1), regulation of actin
cytoskeleton (FGD5), transmembrane signaling systems (GNAI2) or regulation of
NFkappaB activity (NKIRAS1). Dmitriev et
al. further confirm that mechanism of ccRCC development is linked to
destabilization of genes at chromosome 3, discussed in more detail in the next
paragraph.
Studies described above have identified
a large number of genes methylated in sporadic ccRCC. There is small overlap
between studies and consensus on which genes play a role in its etiology and
whether any of those are of relevance clinically. However, all of the reported
genes are involved in processes often deregulated during tumorigenesis:
apoptosis, proliferation, cell survival and tumor invasion. The Cancer Genome Axis (TCGA) Kidney Renal
Clear Cell Carcinoma (KIRC) database provides an excellent opportunity to
confirm and unify previously obtained results (16). These data include 199
ccRCC tumor/normal paired analyses using the Infinium HumanMethylation27
BeadChip validated on 160 ccRCC tumor/normal paired samples using the Infinium
HumanMethylation450 BeadChip.
Mutations of genes regulating epigenetic
modifications
Non-covalent mechanisms, such as
nucleosome remodeling can change chromatin structure and influence gene
activity by altering the accessibility of regulatory DNA sequences to
transcription factors (34). Currently, there are four known families of ATP-dependent
remodeling complexes, characterized by different core ATPases: SWI/SNF, ISWI,
NURD/Mi-2/CHD and INO80. Mutations of SWI/SNF subunits were documented in
approximately 20% of human cancers (for example, medulloblastoma, breast
cancer), indicating that inactivation of this complex is important in tumor
formation (35). PBRM1 encodes the chromatin targeting subunit (BAF180) of the
ATP-dependent SWI/SNF chromatin remodeling complex, implicated in
proliferation, replication, transcription and DNA repair (Figure 1) (36). Truncating mutations in PBRM1 have been found in
88/257 (34%) of ccRCC cases (10). Further studies have shown similar mutation
frequencies, making it the second most commonly altered gene in ccRCC, next to
VHL (37). However, there is no significant correlation between lack
of PBRM1 expression and VHL mutations, and PBRM1 mutations occur at similar
rates in tumors with or without VHL mutations (38). Functional in vitro assays in ccRCC cell lines with
PBRM1 silenced via siRNA resulted in
a significant increase of proliferation in ACHN and 786-O cell lines (with wild
type PBRM1) but not in A704 with a homozygous PBRM1 truncating mutation (10).
In turn, reintroduction of PBRM1 into cells induced the cyclin-dependent kinase
inhibitor p21 expression and led to reduction in cell proliferation (39). PBRM1
silencing results also in increased colony formation in soft agar and increases
cell migration in 786-O, SN12C and TK10 cells, suggesting a tumor suppressive
role for PBRM1 in ccRCC (10). Additionally, ccRCCs deficient in PBRM1 are
associated with a distinct gene-expression signature enriched for genes
implicated in the cytoskeleton and cell motility (40). However, how loss of
PBRM1 function affects chromatin modulation patterns and promotes tumorigenesis
is unknown.
Figure 1.
Schematic representation of epigenetic changes identified in ccRCC tumors. DNMTs
- DNA methyltransferases; HDMs - histone demethylases; HMTs - histone
methyltransferases; Hubs - histone ubiquitinases; HDUbs - histone
deubiquitinases; SWI/SNF - chromatin remodeling complex.
In a small proportion of ccRCCs, ARID1A
(1p35) encoding for different subunit of the SWI/SNF complex (BAF250A) was also
found to be mutated (Figure 1) (10).
In another study, in 16% patients with ccRCC, ARID1A copy number loss was
detected - 67% of tumors (n=79) had significantly lower expression of BAF250A
than control tissue, and in approximately 70% (n=404) decreased ARID1A mRNA
expression was found (41, 42). ARID1A mutations are present at high frequency in
other cancers, for example, ovarian clear cell carcinomas (50%), ovarian
endometrioid carcinomas (30%), and gastric cancers (29%), and studies have
suggested its roles in proliferation, differentiation, and apoptosis (43). The
mechanism of ARID1A alterations and their role in ccRCC pathogenesis is still
unclear.
Besides chromatin remodeling, histone
modifications, controlled by balanced activity of histone modifying enzymes,
also play a critical role in maintaining the proper functioning of cells (44). Most
common N-terminal tail modifications include acetylation and methylation of
lysine or arginine and serine phosphorylation (45). Depending on their type and
location, modifications may influence the accessibility of chromatin or can
recruit and/or block non-histone effector proteins. Various enzymes are responsible
for this dynamic regulation, for example, histone acetyltransferases (HATs) and
methyltransferases (HMTs) that add acetyl and methyl groups, respectively, as
well as enzymes removing these groups: histone deacethylases (HDACs) and
demethylases (HDMs) (46). Altered expression of some of those have been
discovered in ccRCC, including SETD2 and MLL2 (methyltransferases) as well as
JARID1C/KDM5C and UTX/KDM6A (demethylases) (Figure
1).
SETD2 (SET domain containing protein 2)
is mutated in approximately 3% to 8% of ccRCC and its inactivation leads to
loss or decrease of trimethylation of lysine 36 of histone H3 (H3K36me3) (10,
11, 47). In addition, a connection has been reported between SETD2 mutations
and extensive DNA hypomethylation in ccRCC (16). Similar to VHL and PBRM1,
SETD2 is located on chromosome 3p and it was proposed as a novel TSG in ccRCC.
A meta-analysis based on 5 different studies suggests SETD2 mutations cooperate
with mutations in PBRM1 (48). In addition, Garlinger et al. have shown that distinct SETD2 mutations are present in the
same tumor, suggesting a high selective pressure to mutate SETD2 (49). How its
biallelic inactivation is connected to ccRCC remains unclear. Two studies have
linked SETD2 and H3K36me3 to DNA mismatch repair and microsatellite instability
of tumors (50, 51). This finding was not confirmed by Kanu et al., who suggest a role for SETD2 in nucleosome reassembly,
suppression of replication stress, and the coordination of DNA double-strand
breaks (DSBs) repair by homologous recombination (HR) (52). Findings linking
SETD2 to HR have been also reported by Carvalho et al., who showed it is
required for ATM activation upon formation of DSBs, and for HR repair of DSBs
by promoting the formation of RAD51 filaments. SETD2-mutant ccRCC cells
displayed impaired DNA damage signaling, decreased cell survival after DNA
damage and failure to activate the p53-mediated checkpoint (53). Another
methyltransferase frequently mutated in ccRCC, MLL2 (mixed-lineage leukemia
protein 2, localized at 12q13.12), directs tri-methylation of histone H3 lysine
4 (11). The role of MLL2 in pathogenesis of ccRCC is currently unknown.
TSG function was also suggested for
UTX/KDM6A gene coding for histone demethylase (with 3% mutation frequency in
ccRCC) (11, 54). UTX/KDM6A demethylates H3K27me3 linked with repressed
chromatin. It associates with MLL2 which also interacts with another H3K4
demethylase JARID1C/KDM5C, found to be frequently deactivated in ccRCC. Loss of
JARID1C in 786-O ccRCC cells (VHL -/-) leads to significantly lower
H3K4Me3 levels than in VHL+/+. JARID1C is proposed to have a tumor
suppressor role - its knockdown in 786-O VHL-/- ccRCC cells
significantly enhanced tumor growth in a mice xenograft model (55). Taken
together, these data implicate deregulation of methylation/demethylation of
histone H3 (a major regulator of euchromatin/transcription), as an important
and complex phenomenon in ccRCC etiology.
The BRCA1 Associated Protein-1 (BAP1)
gene is also often mutated in ccRCC (8–14%) (12, 37, 56). It is located at 3p
and codes for a nuclear deubiquitinase targeting H2A, one of the most abundant
ubiquitinated proteins in the nucleus, next to H2B (Figure 1) (57). BAP1 interacts with Host Cell Factor C1 (HCF-1),
which recruits histone-modifying enzymes and serves as a scaffold for chromatin
remodeling complexes, promoting the inhibition of cell proliferation (37).
Interestingly, BAP1 and PBRM1 mutations are mutually exclusive and loss of
either BAP1 or PBRM1 proteins has been observed in approximately 70% of ccRCC
cases (37, 56). Moreover, VHL-deficient mice with one active allele of BAP1
exhibited features of human ccRCC, which suggests an important role of BAP1 in
the pathogenesis of ccRCC (58).
Chromatin organization and chromatin accessibility
changes
Formaldehyde-assisted isolation of
regulatory elements (FAIRE), enables interrogation of chromatin accessibility
changes and is based on isolation of nucleosome-depleted regions of DNA,
harboring regulatory elements (active transcriptional start sites, transcriptional
enhancers, and silencers). Studies using this method showed functional
consequences of mutations in genes encoding chromatin regulatory proteins on
chromatin organization and transcription in human tumors (59). Buck et al.
performed FAIRE on matched pairs of tumor/healthy samples and identified
decreased chromatin accessibility at genes previously associated with ccRCC,
such as PBRM1, SETD2 and MLL2 (60). Array-based methylation analysis on this
same set of tumors revealed that chromatin remodeling can occur in parallel
with methylation or independent of it. Recently, Simon et al. used FAIRE to
define the chromatin landscape in a cohort of 42 primary ccRCC tumors and 7
matched normal tissues, and studied the
possible association of variations in chromatin organization with
mutations in SETD2 (61). Changes in chromatin accessibility were identified
primarily within actively transcribed genes, and increase in chromatin
accessibility was linked to alterations in RNA processing (for example, intron retention
and aberrant splicing), affecting ~25% of all expressed genes. Moreover, in
tumors lacking H3K36me3 decreased nucleosome occupancy proximal to aberrantly
spliced exons was observed. This study links mutations in SETD2 to chromatin
accessibility changes and RNA processing defects.
Epigenetic modifications as markers for ccRCC
diagnosis, prognosis, and surveillance
No effective and noninvasive strategy
for detection and prognosis of ccRCC has been established to date. ccRCC
usually remains asymptomatic until a relatively late stage, therefore early
detection, accurate prediction of disease progression and monitoring are
critical. Potentially, altered expression of recently reported histone
modifiers, might be of clinical relevance (Table
1). ccRCC patients with BAP1 mutations were significantly more likely to
present with advanced clinical stage and metastases, and shorter overall
survival (56, 62). Similarly, PBRM1 downregulation correlated with advanced
tumor stage, low differentiation grade and worse patient outcome while SETD2
mutations correlated with a high relapse rate (38, 56). Moreover, tumors with
expression changes of PBRM1 or BAP1, SETD2 and KDM5C were more likely to
present with stage III disease or higher (62). Analysis of cancer specific
survival (CSS) performed in a large patient cohort of 188 patients and
additionally 421 from TCGA, partially confirmed these initial findings (63).
BAP1 mutations were associated with worse CSS in both cohorts (MSKCC, p=0.002;
TCGA, p=0.002) while SETD2 only in the TCGA cohort (p=0.036). PBRM1 mutations
were not correlated with CSS in this study.
Cancer cells display global alterations
of DNA methylation, therefore methylation profiling may be implemented in ccRCC
biomarker discovery. A specific cancer phenotype designated as the CpG island
methylator phenotype (CIMP) was found in ccRCC. It is characterized by DNA
hypermethylation of 17 marker genes and by more aggressive tumors, poorer
patient outcome, and a higher probability of both, recurrence and
disease-related death. ccRCC-CIMP was validated and could be useful for
diagnosis and prognostication of the patients (64, 65). A vast amount of
aberrantly methylated genes, described in previous paragraphs and exemplified
in Table 1, may potentially serve as
biomarkers (4, 18, 66, 67). However, to predict methylation
specificity/sensitivity and thus diagnostic potential, these data require more
detailed investigation.
Most studies on both mutation status of
histone modifiers and gene methylation were conducted on tissue samples. Fluid
based biomarkers for detection, staging and progression monitoring would be
more attractive due to easy, non-invasive acquisition. Nevertheless, to date only
a limited number of studies aimed at finding specific ccRCC biomarkers in blood
or urine has been executed. Methylation-based biomarker candidates found in
urine and serum of ccRCC patients, for example,
INK4, SFRP1, and SFRP2 were reviewed by Baldewijns et al. in 2008 (4). Recently, to our knowledge, only two more
reports have been published. RASSF1A, and VHL (detected in serum) as well as
KILLIN, and LINE-1 (detected in peripheral blood) have been proposed as
predictive biomarkers (68-70). Their association with ccRCC is suggested by
significantly higher levels of promoter hypermethylation in ccRCC patients than
in patients with benign tumors and healthy controls, respectively. High throughput
screening strategies that revealed many new ccRCC biomarker candidates, give
hope that in the near future exploration of fluid based epigenetic biomarkers
will be intensified.
Table
1. Genes involved in epigenetic DNA and
chromatin modifications, proposed as potential biomarkers in ccRCC (a
genes with methylation frequency above 30%).
Epigenetic therapies
Studies that highlighted importance of epigenetic
modifications in the pathogenesis of ccRCC provided new potential objects for
therapeutic intervention. Cancer cells, including ccRCC, are generally
characterized by the overexpression of HDACs leading to decreased histone
acetylation and consequently silencing of genes involved in the regulation of
key cancer pathways (71, 72). Several studies proved the efficacy of some HDAC
inhibitors in reducing tumor growth in cancer patients in phase I and II
clinical trials (72-74). Currently, HDACs are intensively explored as targets
of ccRCC therapy (67, 75). Monotherapies such as, with panobinostat, did not
bring satisfactory results to date. A phase II study enrolled 20 patients with
metastatic refractory ccRCC, previously treated with mTOR inhibitor(s). In the
first evaluation, five patients showed stable disease and three patients
experienced progression. Treatment was generally well tolerated but the median
progression-free survival was limited to 17 months. Hence, panobinostat is
recommended only in combination with other anticancer drugs (76). Also
depsipeptide, tested in 29 patients with metastatic RCC (ccRCC n=25) in a phase
II study, did not show satisfactory results as a monotherapy. The overall
treatment response rate was 7%, in addition severe side effects like fatigue,
nausea, vomiting, anemia were observed (77).
Combined treatment approaches with HDAC
inhibitors seem to be more effective than monotherapy. In models of RCC, the
HDAC inhibitor vorinostat improved the anticancer activity of temsirolimus
(78). Reduced cell viability, clonogenic survival and increased cell death was
observed in RCC cell lines (86-O, A498, 769-P, Caki-1, Caki-2, SW839, ACHN,
G401 and SK-NEP-1) in response to combined treatment. In xenografts of RCC cell
lines (786-O and Caki-1), vorinostat inhibited tumor cell proliferation,
induced apoptosis and impaired angiogenesis, through a decrease in HIF-2a
expression and vessel density. In vitro
and in vivo studies have also shown
that a combination of retinoic acid and HDAC inhibitor trichostatin A is more
efficient than each drug alone (79). The combined therapy enhanced the retinoic
acid pathway signaling, leading to a reduction of proliferation of human RCC
cells lines (SK-RC-39 and SK-RC-45), inhibition of tumor model growth
(SK-RC-39) and increased apoptosis. In combination with retinoids, also MS-275,
a benzamine derivative HDAC inhibitor, showed a better inhibitory effect on
tumor growth in vivo. This effect
persisted after treatment withdrawal, and after continuous treatment in animals
RCC1.18 tumor progression was not observed (80). Interestingly, an induction of
retinoic acid receptor beta was observed during treatment, suggesting HDAC
inhibitors might revert retinoid resistance.
There are also attempts to develop drugs
selectively targeting other enzymes involved in epigenetic modulation,
especially histone methyltransferases or histone demethylases. There are a few
methyltransferase inhibitors showing promising results in cancer models (75,
81). In ccRCC, the S‑adenosylhomocysteine hydrolase inhibitor, 3‑deazaneplanocin
A (DZNep), depletes cellular levels of the enhancer of zeste homologue 2
(EZH2). EZH2 is a catalytic subunit of the polycomb repressive complex 2
(PRC2), a histone methyltransferase that catalyzes tri-methylation of lysine 27
on histone 3 (82). DZNep reduces H3K27 trimethylation levels, additionally, RCC
cells exposed to DZNep showed a significant decrease of cell migration and
invasion in vitro, as well as inhibition of tumor growth, and prolonged survival
in the in vivo mice model.
In a recent report published by
Adelaiye et al., resistance to
sunitinib was studied in mice bearing two different patient-derived ccRCC
xenografts (83). Increasing the drug dose led to partial overcome of initial
sunitinib-induced resistance, suggesting its association with epigenetic
changes such as overexpression of the methyltransferase EZH2 and modulation of
histone marks. Moreover, specific EZH2 inhibition resulted in increased in
vitro anti-tumor effect of sunitinib. These promising results indicate that
high throughput screening strategies could be used to identify further
drug-candidates.
Perspectives
Availability of high-throughput methods
have facilitated investigation of epigenetic modifications in general. The
Roadmap Epigenomics Program recently published mapped epigenomes of 111 types
of primary human healthy cells and tissues, providing valuable reference
epigenome maps (84), moreover many epigenome-wide association studies (EWASs)
initiated in various diseases are currently intensively conducted (85).
Epigenetic studies have also widely broadened our understanding of the biology
of ccRCC, providing evidence of various DNA mutation and methylation events,
chromatin alterations and changes of DNA accessibility, and altogether
suggesting that epigenetic alterations are connected to ccRCC
pathogenesis/progression and require further detailed examination. A number of
new large-scale projects seeking RCC biomarkers are currently ongoing, for
example, CAGEKID, “Biomarker pipeline” (NIH), EuroTARGET or the PREDICT
consortium (66, 86-89). These studies are expected to identify and characterize
novel candidate biomarkers for ccRCC detection, staging and monitoring.
Conflict of interest
None
References
1. Mathew A, Devesa SS, Fraumeni JF,
Jr., Chow WH. Global increases in kidney cancer incidence, 1973-1992. Eur J Cancer
Prev 2002; 11(2):171-178. Doi: http://dx.doi.org/10.1097/00008469-200204000-00010
2. Sun M et al. Age-adjusted incidence,
mortality, and survival rates of stage-specific renal cell carcinoma in North
America: a trend analysis. Eur Urol 2011; 59(1):135-141.
Doi: http:/.dx.doi.org/10.1016/j.eururo.2010.10.029
3. Ferlay J SI, Ervik M, Dikshit R,
Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. (2012 v1.0) GLOBOCAN
Cancer Incidence and Mortality Worldwide: IARC CancerBase No 11. Internet
4. Baldewijns MM, van Vlodrop IJ,
Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M. Genetics and
epigenetics of renal cell cancer. Biochim Biophys Acta 2008; 1785(2):133-155.
Doi: http://dx.doi.org/10.1016/j.bbcan.2007.12.002
5. Brugarolas J. Renal-cell
carcinoma--molecular pathways and therapies. N Engl J Med 2007; 356(2):185-187. Doi: http://dx.doi.org/10.1056/NEJMe068263
6. Motzer RJ. New perspectives on the
treatment of metastatic renal cell carcinoma: an introduction and historical
overview. Oncologist 2011; 16 Suppl 2:1-3.
Doi: http://dx.doi.org/10.1634/theoncologist.2011-S2-01
7. Wood CG. Multimodal approaches in
the management of locally advanced and metastatic renal cell carcinoma:
combining surgery and systemic therapies to improve patient outcome. Clin
Cancer Res 2007; 13(2 Pt 2):697s-702s. Doi: http://dx.doi.org/10.1158/1078-0432.CCR-06-2109
8. Weiss RH, Lin PY. Kidney cancer:
identification of novel targets for therapy. Kidney Int 2006; 69(2):224-232. Doi: http://dx.doi.org/10.1038/sj.ki.5000065
9. Gossage L, Eisen T, Maher ER. VHL,
the story of a tumour suppressor gene. Nat Rev Cancer 2015; 15(1):55-64. Doi: http://dx.doi.org/10.1038/nrc3844
10. Varela I et al. Exome sequencing
identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal
carcinoma. Nature 2011; 469(7331):539-542. Doi: http://dx.doi.org/10.1038/nature09639
11. Dalgliesh GL et al. Systematic
sequencing of renal carcinoma reveals inactivation of histone modifying genes.
Nature 2010; 463(7279):360-363. Doi: http://dx.doi.org/10.1038/nature08672
12. Guo G et al. Frequent mutations of
genes encoding ubiquitin-mediated proteolysis pathway components in clear cell
renal cell carcinoma. Nat Genet 2012; 44(1):17-19.
Doi: http://dx.doi.org/10.1038/ng.1014
13. Herman JG et al. Silencing of the
VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad
Sci U S A 1994; 91(21):9700-9704.
Doi: http://dx.doi.org/10.1073/pnas.91.21.9700
14. Kouzarides T. Chromatin
modifications and their function. Cell 2007; 128(4):693-705. Doi: http://dx.doi.org/10.1016/j.cell.2007.02.005
15. Sharma S, Kelly TK, Jones PA.
Epigenetics in cancer. Carcinogenesis 2010; 31(1):27-36. Doi: http://dx.doi.org/10.1093/carcin/bgp220
16. Comprehensive molecular
characterization of clear cell renal cell carcinoma. Nature 2013;
499(7456):43-49. Doi: http://dx.doi.org/10.1038/nature12222
17. Ricketts CJ, Hill VK, Linehan WM.
Tumor-specific hypermethylation of epigenetic biomarkers, including SFRP1,
predicts for poorer survival in patients from the TCGA Kidney Renal Clear Cell
Carcinoma (KIRC) project. PLoS One 2014; 9(1):e85621. Doi: http://dx.doi.org/10.1371/journal.pone.0085621
18. Rydzanicz M, Wrzesinski T, Bluyssen
HA, Wesoly J. Genomics and epigenomics of clear cell renal cell carcinoma:
recent developments and potential applications. Cancer Lett 2013;
341(2):111-126.
Doi: http://dx.doi.org/10.1016/j.canlet.2013.08.006
19. Bird A. DNA methylation patterns
and epigenetic memory. Genes Dev 2002; 16(1):6-21. Doi: http://dx.doi.org/10.1101/gad.947102
20. Bock C. Analysing and interpreting
DNA methylation data. Nat Rev Genet 2012; 13(10):705-719. Doi: http://dx.doi.org/10.1038/nrg3273
21. Jones PA. Functions of DNA
methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012;
13(7):484-492. Doi: http://dx.doi.org/10.1038/nrg3230
22. Okano M, Bell DW, Haber DA, Li E.
DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation
and mammalian development. Cell 1999; 99(3):247-257.
Doi: http://dx.doi.org/10.1016/S0092-8674(00)81656-6
23. Kim GD, Ni J, Kelesoglu N, Roberts
RJ, Pradhan S. Co-operation and communication between the human maintenance and
de novo DNA (cytosine-5) methyltransferases. EMBO J 2002; 21(15):4183-4195.
Doi: http://dx.doi.org/10.1093/emboj/cdf401
24. Wang Y, Leung FC. An evaluation of
new criteria for CpG islands in the human genome as gene markers. Bioinformatics
2004; 20(7):1170-1177. Doi: http://dx.doi.org/10.1093/bioinformatics/bth059
25. Tsai HC, Baylin SB. Cancer
epigenetics: linking basic biology to clinical medicine. Cell Res 2011;
21(3):502-517. Doi: http://dx.doi.org/10.1038/cr.2011.24
26. Clifford SC, Prowse AH, Affara NA,
Buys CH, Maher ER. Inactivation of the von Hippel-Lindau (VHL) tumour
suppressor gene and allelic losses at chromosome arm 3p in primary renal cell
carcinoma: evidence for a VHL-independent pathway in clear cell renal
tumourigenesis. Genes Chromosomes Cancer 1998; 22(3):200-209. Doi: http://dx.doi.org/10.1002/(SICI)1098-2264(199807)22:3<200::AID-GCC5>3.0.CO;2-#
27. Nickerson ML et al. Improved
identification of von Hippel-Lindau gene alterations in clear cell renal
tumors. Clin Cancer Res 2008; 14(15):4726-4734. Doi: http://dx.doi.org/10.1158/1078-0432.CCR-07-4921
28. Morris MR, Maher ER. Epigenetics of
renal cell carcinoma: the path towards new diagnostics and therapeutics. Genome
Med 2010; 2(9):59. Doi: http://dx.doi.org/10.1186/gm180
29. Morris MR, Ricketts C, Gentle D,
Abdulrahman M, Clarke N, Brown M, Kishida T, Yao M, Latif F, Maher ER.
Identification of candidate tumour suppressor genes frequently methylated in
renal cell carcinoma. Oncogene 2010; 29(14):2104-2117. Doi: http://dx.doi.org/10.1038/onc.2009.493
30. Morris MR et al. Genome-wide
methylation analysis identifies epigenetically inactivated candidate tumour
suppressor genes in renal cell carcinoma. Oncogene 2011; 30(12):1390-1401.
Doi:
http://dx.doi.org/10.1038/onc.2010.525
31. McRonald FE et al. CpG methylation
profiling in VHL related and VHL unrelated renal cell carcinoma. Mol Cancer
2009; 8:31. Doi: http://dx.doi.org/10.1186/1476-4598-8-31
32. Ricketts CJ, Morris MR, Gentle D,
Brown M, Wake N, Woodward ER, Clarke N, Latif F, Maher ER. Genome-wide CpG
island methylation analysis implicates novel genes in the pathogenesis of renal
cell carcinoma. Epigenetics 2012; 7(3):278-290. Doi:http://dx.doi.org/10.4161/epi.7.3.19103
33. Dmitriev AA et al. Epigenetic
alterations of chromosome 3 revealed by NotI-microarrays in clear cell renal
cell carcinoma. Biomed Res Int 2014; 2014:735292. Doi: http://dx.doi.org/10.1155/2014/735292
34. Jiang C, Pugh BF. Nucleosome
positioning and gene regulation: advances through genomics. Nat Rev Genet 2009;
10(3):161-172. Doi: http://dx.doi.org/10.1038/nrg2522
35. Hohmann AF, Vakoc CR. A rationale
to target the SWI/SNF complex for cancer therapy. Trends Genet 2014;
30(8):356-363.
Doi: http://dx.doi.org/10.1016/j.tig.2014.05.001
36. Reisman D, Glaros S, Thompson EA.
The SWI/SNF complex and cancer. Oncogene 2009; 28(14):1653-1668. Doi: http://dx.doi.org/10.1038/onc.2009.4
37. Pena-Llopis S et al. BAP1 loss
defines a new class of renal cell carcinoma. Nat Genet 2012; 44(7):751-759. Doi: http://dx.doi.org/10.1038/ng.2323
38. Pawlowski R, Muhl SM, Sulser T,
Krek W, Moch H, Schraml P. Loss of PBRM1 expression is associated with renal
cell carcinoma progression. Int J Cancer 2013; 132(2):E11-17.
Doi: http://dx.doi.org/10.1002/ijc.27822
39. Xia W, Nagase S, Montia AG,
Kalachikov SM, Keniry M, Su T, Memeo L, Hibshoosh H, Parsons R. BAF180 is a
critical regulator of p21 induction and a tumor suppressor mutated in breast
cancer. Cancer Res 2008; 68(6):1667-1674. Doi: http://dx.doi.org/10.1158/0008-5472.CAN-07-5276
40. Kapur P, Pena-Llopis S, Christie A,
Zhrebker L, Pavia-Jimenez A, Rathmell WK, Xie XJ, Brugarolas J. Effects on
survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell
carcinoma: a retrospective analysis with independent validation. Lancet Oncol
2013; 14(2):159-167. Doi: http://dx.doi.org/10.1016/S1470-2045(12)70584-3
41. Lichner Z, Scorilas A, White NM,
Girgis AH, Rotstein L, Wiegand KC, Latif A, Chow C, Huntsman D, Yousef GM. The
chromatin remodeling gene ARID1A is a new prognostic marker in clear cell renal
cell carcinoma. Am J Pathol 2013; 182(4):1163-1170. Doi: http://dx.doi.org/10.1016/j.ajpath.2013.01.007
42. Girgis AH et al. Multilevel
whole-genome analysis reveals candidate biomarkers in clear cell renal cell
carcinoma. Cancer Res 2012; 72(20):5273-5284. Doi: http://dx.doi.org/10.1158/0008-5472.CAN-12-0656
43. Wu JN, Roberts CW. ARID1A mutations
in cancer: another epigenetic tumor suppressor? Cancer Discov 2013; 3(1):35-43.
Doi: http://dx.doi.org/10.1158/2159-8290.CD-12-0361
44. Kelly TK, De Carvalho DD, Jones PA.
Epigenetic modifications as therapeutic targets. Nat Biotechnol 2010;
28(10):1069-1078. Doi: http://dx.doi.org/10.1038/nbt.1678
45. Ruthenburg AJ, Li H, Patel DJ,
Allis CD. Multivalent engagement of chromatin modifications by linked binding
modules. Nat Rev Mol Cell Biol 2007; 8(12):983-994. Doi: http://dx.doi.org/10.1038/nrm2298
46. Haberland M, Montgomery RL, Olson
EN. The many roles of histone deacetylases in development and physiology:
implications for disease and therapy. Nat Rev Genet 2009; 10(1):32-42.
Doi: http://dx.doi.org/10.1038/nrg2485
47. Duns G, van den Berg E, van
Duivenbode I, Osinga J, Hollema H, Hofstra RM, Kok K. Histone methyltransferase
gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma.
Cancer Res 2010; 70(11):4287-4291. Doi: http://dx.doi.org/10.1158/0008-5472.CAN-10-0120
48. Pena-Llopis S, Christie A, Xie XJ,
Brugarolas J. Cooperation and antagonism among cancer genes: the renal cancer
paradigm. Cancer Res 2013; 73(14):4173-4179.
Doi: http://dx.doi.org/10.1158/0008-5472.CAN-13-0360
49. Gerlinger M et al. Intratumor
heterogeneity and branched evolution revealed by multiregion sequencing. N Engl
J Med 2012; 366(10):883-892. Doi: http://dx.doi.org/10.1056/NEJMoa1113205
50. Li F, Mao G, Tong D, Huang J, Gu L,
Yang W, Li GM. The histone mark H3K36me3 regulates human DNA mismatch repair
through its interaction with MutSalpha. Cell 2013; 153(3):590-600.
Doi: http://dx.doi.org/10.1016/j.cell.2013.03.025
51. Alexandrov LB et al. Signatures of
mutational processes in human cancer. Nature 2013; 500(7463):415-421. Doi: http://dx.doi.org/10.1038/nature12477
52. Kanu N et al. SETD2
loss-of-function promotes renal cancer branched evolution through replication
stress and impaired DNA repair. Oncogene 2015. Doi: http://dx.doi.org/10.1038/onc.2015.24
53. Carvalho S, Vitor AC, Sridhara SC,
Martins FB, Raposo AC, Desterro JM, Ferreira J, de Almeida SF. SETD2 is
required for DNA double-strand break repair and activation of the p53-mediated
checkpoint. Elife 2014; 3:e02482. Doi: http://dx.doi.org/10.7554/eLife.02482
54. van Haaften G et al. Somatic
mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet
2009; 41(5):521-523. Doi: http://dx.doi.org/10.1038/ng.349
55. Niu X, Zhang T, Liao L, Zhou L,
Lindner DJ, Zhou M, Rini B, Yan Q, Yang H. The von Hippel-Lindau tumor
suppressor protein regulates gene expression and tumor growth through histone
demethylase JARID1C. Oncogene 2012; 31(6):776-786. Doi: http://dx.doi.org/10.1038/onc.2011.266
56. Sato Y et al. Integrated molecular
analysis of clear-cell renal cell carcinoma. Nat Genet 2013; 45(8):860-867. Doi: http://dx.doi.org/10.1038/ng.2699
57. Cao J, Yan Q. Histone
ubiquitination and deubiquitination in transcription, DNA damage response, and
cancer. Front Oncol 2012; 2:26.
Doi: http://dx.doi.org/10.3389/fonc.2012.00026
58. Wang SS et al. Bap1 is essential
for kidney function and cooperates with Vhl in renal tumorigenesis. Proc Natl
Acad Sci U S A 2014; 111(46):16538-16543.
Doi: http://dx.doi.org/10.1073/pnas.1414789111
59. Simon JM, Giresi PG, Davis IJ, Lieb
JD. Using formaldehyde-assisted isolation of regulatory elements (FAIRE) to
isolate active regulatory DNA. Nat Protoc 2012; 7(2):256-267.
Doi: http://dx.doi.org/10.1038/nprot.2011.444
60. Buck MJ, Raaijmakers LM,
Ramakrishnan S, Wang D, Valiyaparambil S, Liu S, Nowak NJ, Pili R. Alterations
in chromatin accessibility and DNA methylation in clear cell renal cell
carcinoma. Oncogene 2014; 33(41):4961-4965. Doi: http://dx.doi.org/10.1038/onc.2013.455
61. Simon JM et al. Variation in
chromatin accessibility in human kidney cancer links H3K36 methyltransferase
loss with widespread RNA processing defects. Genome Res 2014; 24(2):241-250.
Doi: http://dx.doi.org/10.1101/gr.158253.113
62. Hakimi AA et al. Clinical and
pathologic impact of select chromatin-modulating tumor suppressors in clear
cell renal cell carcinoma. Eur Urol 2013; 63(5):848-854.
Doi: http://dx.doi.org/10.1016/j.eururo.2012.09.005
63. Hakimi AA et al. Adverse outcomes
in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators
BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin
Cancer Res 2013; 19(12):3259-3267. Doi: http://dx.doi.org/10.1158/1078-0432.CCR-12-3886
64. Arai E, Chiku S, Mori T, Gotoh M,
Nakagawa T, Fujimoto H, Kanai Y. Single-CpG-resolution methylome analysis
identifies clinicopathologically aggressive CpG island methylator phenotype
clear cell renal cell carcinomas. Carcinogenesis 2012; 33(8):1487-1493. Doi: http://dx.doi.org/10.1093/carcin/bgs177
65. Tian Y, Arai E, Gotoh M, Komiyama
M, Fujimoto H, Kanai Y. Prognostication of patients with clear cell renal cell
carcinomas based on quantification of DNA methylation levels of CpG island
methylator phenotype marker genes. BMC Cancer 2014; 14:772. Doi: http://dx.doi.org/10.1186/1471-2407-14-772
66. Vasudev NS, Selby PJ, Banks RE.
Renal cancer biomarkers: the promise of personalized care. BMC Med 2012;
10:112. Doi: http://dx.doi.org/10.1186/1741-7015-10-112
67. Vieira-Coimbra M, Henrique R,
Jeronimo C. New insights on chromatin modifiers and histone post-translational
modifications in renal cell tumours. Eur J Clin Invest 2015; 45 Suppl 1:16-24.
Doi: http://dx.doi.org/10.1111/eci.12360
68. de Martino M, Klatte T, Haitel A,
Marberger M. Serum cell-free DNA in renal cell carcinoma: a diagnostic and
prognostic marker. Cancer 2012; 118(1):82-90. Doi: http://dx.doi.org/10.1002/cncr.26254
69. Bennett KL, Campbell R, Ganapathi
S, Zhou M, Rini B, Ganapathi R, Neumann HP, Eng C. Germline and somatic DNA
methylation and epigenetic regulation of KILLIN in renal cell carcinoma. Genes
Chromosomes Cancer 2011; 50(8):654-661. Doi: http://dx.doi.org/10.1002/gcc.20887
70. Liao LM et al. LINE-1 methylation
levels in leukocyte DNA and risk of renal cell cancer. PLoS One 2011;
6(11):e27361. Doi: http://dx.doi.org/10.1371/journal.pone.0027361
71. Fritzsche FR et al. Class I histone
deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer
2008; 8:381. Doi: http://dx.doi.org/10.1186/1471-2407-8-381
72. Minardi D, Lucarini G, Filosa A,
Milanese G, Zizzi A, Di Primio R, Montironi R, Muzzonigro G. Prognostic role of
global DNA-methylation and histone acetylation in pT1a clear cell renal
carcinoma in partial nephrectomy specimens. J Cell Mol Med 2009; 13(8B):2115-2121.
Doi: http://dx.doi.org/10.1111/j.1582-4934.2008.00482.x
73. Jones J, Juengel E, Mickuckyte A,
Hudak L, Wedel S, Jonas D, Blaheta RA. The histone deacetylase inhibitor
valproic acid alters growth properties of renal cell carcinoma in vitro and in
vivo. J Cell Mol Med 2009; 13(8B):2376-2385. Doi: http://dx.doi.org/10.1111/j.1582-4934.2008.00436.x
74. Siu LL et al. Phase I study of
MGCD0103 given as a three-times-per-week oral dose in patients with advanced
solid tumors. J Clin Oncol 2008; 26(12):1940-1947.
Doi: http://dx.doi.org/10.1200/JCO.2007.14.5730
75. Larkin J, Goh XY, Vetter M,
Pickering L, Swanton C. Epigenetic regulation in RCC: opportunities for
therapeutic intervention? Nat Rev Urol 2012; 9(3):147-155.
Doi: http://dx.doi.org/10.1038/nrurol.2011.236
76. Hainsworth JD, Infante JR, Spigel
DR, Arrowsmith ER, Boccia RV, Burris HA. A phase II trial of panobinostat, a
histone deacetylase inhibitor, in the treatment of patients with refractory
metastatic renal cell carcinoma. Cancer Invest 2011; 29(7):451-455. Doi: http://dx.doi.org/10.3109/07357907.2011.590568
77. Stadler WM, Margolin K, Ferber S,
McCulloch W, Thompson JA. A phase II study of depsipeptide in refractory
metastatic renal cell cancer. Clin Genitourin Cancer 2006; 5(1):57-60.
Doi: http://dx.doi.org/10.3816/CGC.2006.n.018
78. Mahalingam D et al. Vorinostat
enhances the activity of temsirolimus in renal cell carcinoma through
suppression of survivin levels. Clin Cancer Res 2010; 16(1):141-153.
Doi: http://dx.doi.org/10.1158/1078-0432.CCR-09-1385
79. Touma SE, Goldberg JS, Moench P,
Guo X, Tickoo SK, Gudas LJ, Nanus DM. Retinoic acid and the histone deacetylase
inhibitor trichostatin a inhibit the proliferation of human renal cell
carcinoma in a xenograft tumor model. Clin Cancer Res 2005; 11(9):3558-3566. Doi: http://dx.doi.org/10.1158/1078-0432.CCR-04-1155
80. Wang XF, Qian DZ, Ren M, Kato Y,
Wei Y, Zhang L, Fansler Z, Clark D, Nakanishi O, Pili R. Epigenetic modulation
of retinoic acid receptor beta2 by the histone deacetylase inhibitor MS-275 in
human renal cell carcinoma. Clin Cancer Res 2005; 11(9):3535-3542. Doi: http://dx.doi.org/10.1158/1078-0432.CCR-04-1092
81. Spannhoff A, Sippl W, Jung M.
Cancer treatment of the future: inhibitors of histone methyltransferases. Int J
Biochem Cell Biol 2009; 41(1):4-11.
Doi: http://dx.doi.org/10.1016/j.biocel.2008.07.024
82. Liu L, Xu Z, Zhong L, Wang H, Jiang
S, Long Q, Xu J, Guo J. EZH2 promotes tumor cell migration and invasion via
epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int 2014.
Doi: http://dx.doi.org/10.1111/bju.12702
83. Adelaiye R et al. Sunitinib dose
escalation overcomes transient resistance in clear cell renal cell carcinoma
and is associated with epigenetic modifications. Mol Cancer Ther 2015;
14(2):513-522.
Doi: http://dx.doi.org/10.1158/1535-7163.MCT-14-0208
84. Kundaje A et al. Integrative
analysis of 111 reference human epigenomes. Nature 2015; 518(7539):317-330. Doi: http://dx.doi.org/10.1038/nature14248
85. Paul DS, Beck S. Advances in
epigenome-wide association studies for common diseases. Trends Mol Med 2014;
20(10):541-543. Doi: http://dx.doi.org/10.1016/j.molmed.2014.07.002
86. CAGEKID. http://www.cng.fr/cagekid/index.html/
87. Biomarker pipeline. http://www.biomarkerpipeline.org/nihr/
88. EuroTARGET.http://www.eurotargetproject.eu/
89. PREDICT consortium.http://www.predictconsortium.eu/
90. Hirata H et al. Wnt antagonist DKK1
acts as a tumor suppressor gene that induces apoptosis and inhibits
proliferation in human renal cell carcinoma. Int J Cancer 2011;
128(8):1793-1803.
Doi: http://dx.doi.org/10.1002/ijc.25507
91. Hirata H et al. Wnt antagonist gene
DKK2 is epigenetically silenced and inhibits renal cancer progression through
apoptotic and cell cycle pathways. Clin Cancer Res 2009; 15(18):5678-5687.
Doi: http://dx.doi.org/10.1158/1078-0432.CCR-09-0558
92. Urakami S et al. Wnt antagonist
family genes as biomarkers for diagnosis, staging, and prognosis of renal cell
carcinoma using tumor and serum DNA. Clin Cancer Res 2006; 12(23):6989-6997.
Doi: http://dx.doi.org/10.1158/1078-0432.CCR-06-1194
93. Christoph F, Weikert S,
Kempkensteffen C, Krause H, Schostak M, Kollermann J, Miller K, Schrader M.
Promoter hypermethylation profile of kidney cancer with new proapoptotic p53
target genes and clinical implications. Clin Cancer Res 2006; 12(17):5040-5046.
Doi: http://dx.doi.org/10.1158/1078-0432.CCR-06-0144
94. Ahmad ST, Arjumand W, Seth A, Saini
AK, Sultana S. Methylation of the APAF-1 and DAPK-1 promoter region correlates with
progression of renal cell carcinoma in North Indian population. Tumour Biol
2012; 33(2):395-402. Doi: http://dx.doi.org/10.1007/s13277-011-0235-9
95. Ibanez de Caceres I, Dulaimi E,
Hoffman AM, Al-Saleem T, Uzzo RG, Cairns P. Identification of novel target
genes by an epigenetic reactivation screen of renal cancer. Cancer Res 2006;
66(10):5021-5028.
Doi: http://dx.doi.org/10.1158/0008-5472.CAN-05-3365
96. Yoo KH, Park YK, Kim HS, Jung WW,
Chang SG. Epigenetic inactivation of HOXA5 and MSH2 gene in clear cell renal
cell carcinoma. Pathol Int 2010; 60(10):661-666.
Doi: http://dx.doi.org/10.1111/j.1440-1827.2010.02578.x
97. Zhang Q, Ying J, Li J, Fan Y, Poon
FF, Ng KM, Tao Q, Jin J. Aberrant promoter methylation of DLEC1, a critical
3p22 tumor suppressor for renal cell carcinoma, is associated with more
advanced tumor stage. J Urol 2010; 184(2):731-737. Doi: http://dx.doi.org/10.1016/j.juro.2010.03.108
98. van Vlodrop IJ et al. Prognostic
significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear
cell renal cell carcinoma. Am J Pathol 2010; 176(2):575-584.
Doi: http://dx.doi.org/10.2353/ajpath.2010.090442
99. Gossage L et al. Clinical and
pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear
cell renal cell carcinoma. Genes Chromosomes Cancer 2014; 53(1):38-51.
Doi: http://dx.doi.org/10.1002/gcc.22116