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EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 52–59
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Epidemiology, Aetiology, and Pathogenesis of Renal Cell
Carcinoma
Chris Protzel, Matthias Maruschke, Oliver W. Hakenberg *
Department of Urology, Rostock University, Germany
Article info
Abstract
Keywords:
Renal cancer
Etiology
VHL gene
Hypermethylation
Folliculin
Significant advances in molecular medicine have made renal cell carcinoma (RCC)
the prototype solid organ malignancy for targeted medical cancer treatment.
Theseis new options have made it possible to prolong the life of patients with
metastatic disease. However, we are far away from thoroughly understanding the
molecular processes of RCC development let alone from being able to cure
advanced renal cancer. RCC is the most common renal neoplasia and it remains
a very aggressive and often fatal disease.
There are several known histologic subtypes of this heterogeneous tumor entity
with associated distinct molecular alterations and different clinical outcomes [1–
4]. The clear cell renal cell carcinoma (ccRCC) is the most common and apparently
most aggressive RCC subtype with the highest rates of local invasion, metastasis
and mortality. It constitutes 70–80% of all renal cancers [1,5]. It is estimated that
more than 30% of patients with RCC have metastatic disease at the time of diagnosis
and 30% of organ-confined RCCs will develop metastatic disease after local treatment [6]. Thus, RCC remains a very major challenge.
# 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author.
E-mail address: [email protected] (O.W. Hakenberg).
1.
Introduction
Significant advances in molecular medicine have made
renal cell carcinoma (RCC) the prototype solid organ
malignancy for targeted medical cancer treatment. These
new options have made it possible to prolong the life of
patients with metastatic disease. However, we are far from
thoroughly understanding the molecular processes of RCC
development, let alone being able to cure advanced renal
cancer. RCC is the most common renal neoplasia, and it
remains a very aggressive and often fatal disease.
There are several known histologic subtypes of this
heterogeneous tumour entity with associated distinct
molecular alterations and different clinical outcomes
[1–4]. Clear cell renal cell carcinoma (ccRCC) is the most
common and apparently the most aggressive RCC subtype
with the highest rates of local invasion, metastasis, and
mortality. It constitutes 70–80% of all renal cancers [1,5]. It
is estimated that >30% of patients with RCC have
metastatic disease at the time of diagnosis, and 30% of
patients with organ-confined RCCs develop metastatic
disease after local treatment [6]. Thus RCC remains a very
major challenge.
2.
Frequency
RCC overall accounts for 2% of all adult malignancies [7].
Worldwide, based on probably incomplete figures, about
270 000 new cases are diagnosed per year, and about 116 000
patients die per year [8]. In the United States alone, 58 000
new RCC cases were diagnosed in 2010, and approximately
13 000 patients died of RCC in the same year [7,9]. This
corresponds to 65 000 new RCC cases per year in the
European Union with >25 000 RCC deaths every year [10].
1569-9056/$ – see front matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eursup.2012.05.002
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EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 52–59
Portugal
3.3
Switzerland
3.6
6.9
8.2
4.4
Spain
9.3
Sweden
6.1
Netherlands
5.9
UK
5.8
9.9
10.8
10.8
6.4
Denmark
10.9
4.3
Greece
11.2
5.2
Norway
13.0
4.7
Italy
14.1
Mortality
6.8
Finland
14.2
Incidence
9.0
Slovakia
15.8
5.6
Germany
16.4
6.7
Belgium
16.5
7.0
Ireland
17.6
5.45
Austria
17.8
7.75
Hungary
17.8
5.37
France
18.8
8.7
Poland
20.0
10.2
Iceland
20.7
14.56
Czech Republic
28.9
0
10
20
30
40
Fig. 1 – Incidence and mortality rates in European countries (modified from Lungberg et al. [10]).
Thus at least 20–40% of patients diagnosed with RCC die of
the disease.
Overall, there are some geographic, racial, and gender
differences in the incidence of RCC. RCC occurs more than
twice as often in men as in women. In Europe, the highest
incidence is seen in the eastern parts of Europe; Portugal
and Spain report the lowest incidence (Fig. 1). The reasons
for this distribution are unclear. The overall incidence rate
for Europe is estimated at 14.5 per 100 000 for men and 6.9
per 100 000 for women [10].
There are some indications that a recent increase in
incidence together with a stage shift to more organconfined stages can be observed [11,12]. An apparent stage
shift is mainly attributed to a more widespread use of
imaging for early detection.
The mortality rates vary, however, among different
European countries (Fig. 1). There is no clear explanation for
this other than perhaps differences in the use of imaging
techniques. As a consequence of the decrease in mortality
rates, the 5-yr survival after RCC treatment has increased
[13–15].
4.
It is poorly understood why people develop RCC. Only a few
aetiologic factors have been clinically identified as risk
factors for RCC. In contrast, the understanding of some
important molecular and genetic factors of RCC development has increased considerably.
4.1.
3.
Aetiology
Demographic factors
Mortality
The mortality from RCC has continually decreased over the
last decades. A recent analysis showed a decline in mortality
rates (death from RCC per unit of the population) from 4.8
per 100 000 in the period 1990–1994 to 4.1 per 100 000 in
2000–2004 in men [10]. This decline in RCC mortality is also
attributed to earlier and the often incidental diagnosis of
small RCCs by imaging.
Age, sex, and race are important factors in RCC development. The incidence of RCC correlates with age, and the
highest incidence is found in the sixth and seventh decades.
About 80% of all RCC patients are between 40 and 69 yr of
age [16]. Due to the increasing life expectancy in many
countries and increased early diagnosis, the peak age of RCC
diagnosis might shift still further into the seventh and
eighth decades of life.
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EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 52–59
RCC is less common in Asia than in Europe or North
America. Asian populations in the United States also show a
lower risk of developing RCC [6]. Although the reported
incidence rate of RCC in Africa is also relatively low, African
Americans in the United States have a higher incidence of
RCC compared with the US white population [6,16,17]. This
may well be multifactorial, and it is presumably related to
the lower rates of imaging use and early RCC diagnosis in
African countries.
4.2.
Toxic substances
Cigarette smoking has been shown to be a significant risk
factor for the development of RCC. A meta-analysis
described a significantly higher risk for ever smoking
compared with never smoking [18]. The risk for renal
cancer increased by 54% in men and 22% in women who
ever were smokers. A clear correlation between high
doses of tobacco smoke and a higher risk was shown [18].
Due to the limited data available, the influence of
smoking cessation for a potential risk reduction as well
as the potential risk of passive smoking remain unclear
[18,19].
Several studies in the 1990s examined occupational
toxicities. An international case-control study demonstrated an increased risk for RCC in people in industries working
with cadmium (relative risk [RR]: 2.0), coke ovens (RR: 1.7),
steel (RR: 1.6), and gasoline/petroleum (RR: 1.6) [20,21]. In
contrast, other studies failed to show an increased risk for
diesel and gasoline exposure or for European asphalt
workers [21,22].
Trichloroethylene (TCE) exposure leads to carcinogenesis in animal models. Although some studies found an
increased RCC risk in populations with high TCE exposure
[10,23], other studies did not confirm this finding. The
exposure to perchloroethylene does not seem to be
associated with an increased risk [24].
Regarding pesticides, a significantly increased risk for
RCC development was reported in a recent case-control
study. Supporting this, a higher risk for RCC was reported in
Asian agricultural workers [25].
4.3.
Obesity and nutritional factors
Several case-control and cohort studies have demonstrated an increased risk for RCC in association with excess
body weight. An estimated increased risk of 1.24 in men
and 1.34 in women per 5 kg/m2 increase in body mass
index was reported in a meta-analysis of prospective
studies [26].
Regarding nutritional factors, there is no reported
association between protein and fat consumption and the
risk of RCC [27]. Vitamins or other supplements did not
show any influence on the incidence either [10]. Only one
case-control study in 2009 reported a possible role of a
genetic polymorphism of the vitamin D receptor gene for
the risk of RCC [28]. Whether this really relates to
nutritional factors is not clear.
Several large studies have examined dietary habits [10].
Only one study reported an inverse association between
fruit and vegetable consumption and the incidence of RCC
[29]; two other studies failed to show such a correlation
[30,31]. There are only insignificant data for fish and meat
consumption in relation to RCC risk. Coffee consumption as
well as total fluid intake is not associated with an increased
risk. However, several studies demonstrated a significant
association between moderate alcohol consumption and an
increased risk of RCC.
5.
Genetic changes in renal cancer
Because several hereditary RCC syndromes are known
(Table 1), genetic and epigenetic changes in the carcinogenesis of renal cancer are strongly suspected [32].
5.1.
The hypoxia inducible factors pathway in clear cell renal
cell carcinoma and the von Hippel-Lindau syndrome
The genetic association of RCC associated with the von
Hippel-Lindau (VHL) gene with chromosomal loss in
3p25-26 was found in 1993 [33]. Mutations of the VHL
gene were also found in 60–80% of sporadic RCC [34]. The
hereditary VHL syndrome leads to hemangioblastomas of
Table 1 – Hereditary renal cancer
Syndrome
Gene
(chromosome)
Tumour type
Von Hippel-Lindau
VHL
(3p25)
Multiple, bilateral ccRCC, renal cysts
Hereditary papillary RCC
Hereditary leiomyomatosis
and RCC
Birt-Hogg-Dubé
c-MET (7p31)
Fumarate
hydratase (1q42)
BHD folliculin
(17p11)
TSC1 (9q34)
TSC2 (16p13)
3p translocation
Multiple, bilateral papillary RCC type 1
Papillary RCC type 2
Tuberous sclerosis
Constitutional translocation
Chromosome 3
(familial ccRCC)
ccRCC = clear cell renal cell carcinoma.
Multiple chromophobe RCC, oncocytic
adenoma, papillary RCC
Multiple, bilateral angiomyolipomas,
lymphangioleiomyomatosis, rare ccRCC
Multiple, bilateral ccRCC
Extrarenal manifestation
Hemangioblastoma of retina and central nervous system,
phaeochromocytoma, neuroendocrine tumours, pancreatic,
renal, epididymal, and parametrial cysts
–
Cutaneous and uterine leiomyomas
Facial fibrofolliculoma, pulmonal cysts
Cutaneous angiofibroma, cardiac rhabdomyoma,
small intestine polyps, pulmonale and renal cysts
–
EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 52–59
55
Fig. 2 – Normal and mutated von Hippel-Lindau (VHL) in cell function. HIF = hypoxia inducible factor; PDGF = platelet-derived growth factor;
VEGF = vascular endothelial growth factor.
the central nervous system; retinal angiomas; benign
tumours of the inner ear, pancreas, and epididymis; and
pheochromocytomas [35].
The VHL protein is a tumour suppressor, which is one
component of the E3 ubiquitin-ligase complex [36,37].
Under normal functional conditions (without mutations)
and a normoxic cell situation, the VHL complex targets the
hypoxia inducible factor (HIF) transcription factors [37].
HIF1a in particular regulates important downstream
targets such as vascular endothelial growth factor (VEGF),
platelet-derived growth factor, and glucose transporter 1
[37]. As a result of VHL gene mutations, HIF accumulates and
leads to a massive stimulation of growth factors (Fig. 2).
Interestingly, HIF1a synthesis is inhibited by the multikinase inhibitor sunitinib [36].
5.2.
5.3.
The fumarate hydratase gene and the hereditary
leiomyomatosis renal cell carcinoma
Mutations in the fumarate hydratase gene (FH), located at
chromosome 1q42, are found in patients with hereditary
leiomyomatosis RCC [37]. FH is a tumour suppressor gene
encoding an important enzyme of the carbohydrate
metabolism of the cell (tricarboxylic acid cycle). Due to
derangement of the mitochondrial conversion of fumarate
to malate, fumarate is overaccumulated, and hypoxia leads
to upregulation of HIF [36,41]. A minority of patients with
FH mutations develop papillary type 2 RCC or collecting
duct tumours that are very aggressive [42]. Other typical
problems of hereditary leiomyomatosis are cutaneous
leiomyomas and, in women, early multiple leiomyomas
of the uterus [10].
The mesenchymal-epithelial transition pathway and
hereditary papillary renal cell carcinoma
5.4.
The proto-oncogene mesenchymal-epithelial transition
(MET) encodes a tyrosine kinase membrane receptor
[36]. The ligand is the hepatocyte growth factor (HGF).
The MET gene is located at chromosome 7q31. Gain-offunction mutations result in a consecutive activation of the
receptor [38,39]. The activation of the signalling cascade
results in multiple tumourigenic processes (eg, angiogenesis). The hereditary papillary RCC syndrome is characterised by bilateral multifocal papillary type 1 tumours.
Interestingly, up to 75% of sporadic papillary RCCs show
trisomy 7 [40]. Multikinase inhibitors and anti-HGF
antibodies are potentially valuable for the future treatment
of papillary RCC [36].
Birt-Hogg-Dubé (BHD) syndrome is characterised by lossof-function mutations in the folliculin gene (FLCN) at
chromosome 17p11.2. Renal tumours of BHD show variable
histology like chromophobe RCC, ccRCC, oncocytoma, and
oncocytic-chromophobe hybrid [37,43].
The function of the protein folliculin is not completely
known [36]. Inactivation of the FLCN gene leads to
polycystic kidney degeneration and renal tumours in mouse
models. A tumour suppressor function has been discussed
[44,45]. An interaction of FLCN with the mammalian target
of rapamycin complex 1 (mTORC1) may play an important
role in nutrient and energy sensing of cells [44,45]. Loss of
FLCN function was shown to be associated with mTORC1
The folliculin gene and the Birt-Hogg-Dubé syndrome
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EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 52–59
Growth
factors
PTEN
PDK1
YY
TK
Growth factor
receptors
TK
PI3K
P
AKT
RICTOR
P
SIN1
mTOR MLST8
mTORC2
TSC2
TSC1
P
S6K1
RAPTOR
mTORC1
RHEB
mTOR MLST8
PRA840
P
4E-BP1
Proliferation
Biosynthesis
Metabolism
Fig. 3 – Mammalian target of rapamycin (mTOR) pathway and cell signalling upstream and downstream with involvement of TORC1 and TORC2.
MTORC2 = mammalian target of rapamycin complex 2; RAPTOR = regulatory-associated protein of mTOR; RICTOR = rapamycin-insensitive companion of
mTOR.
activity during renal tumourigenesis [45–47]. This fact
promises a potential therapeutic role for mTOR inhibitors in
RCC with FLCN gene mutations [36].
5.5.
The phosphatidylinositol-3-kinase/Akt pathway
The phosphatidylinositol-3-kinase/Akt messenger system is
important for the regulation of different cellular processes
of survival and cell cycle regulation. One important target
again is mTOR [36,48]. The Akt–mTOR interaction is
mediated by the tuberous sclerosis heterodimer protein
complex, which suppresses mTOR activity [36]. Changes in
the phosphatidylinositol-3-kinase/Akt pathway are known
to be involved in the oncogenesis of many carcinomas [47].
5.6.
The mammalian target of rapamycin pathway
MTOR is a multifunctional serine-threonine kinase that
plays a central role in the regulation of cell growth,
proliferation, apoptosis, and metabolism of the cell.
Consequently, mTOR is also involved in renal carcinogenesis
by the modulation of expression and stability of oncogenic
proteins such as HIF, VEGF, cyclin D, and c-MYC [49,50].
mTOR forms multimolecular complexes with raptor (regulatory-associated protein of mTOR) to form mTORC1 and
with rictor (rapamycin-insensitive companion of mTOR) to
form another multimolecular complex named mTORC2. The
activation of mTOR results from the phosphatidylinositol 3kinase (PI3K) pathway by growth factors receptors such as
epidermal growth factor receptor (EGFR) or insulinlike
growth factor receptor (IGFR). The activated mTORC1
complex phosphorylates its downstream effectors, for
example, eukaryotic translation initiation factor 4E-binding
protein (4EBP1) and S6 kinase 1 (S6K1). This mTOR
activation downstream leads to an increased translation
of messenger RNA and protein biosynthesis, increasing
metabolism and energy balance as well as decreasing
autophagy (Fig. 3) [51,52].
5.7.
Other genetic aberrations
Constitutional chromosome 3 translocations are also found
in patients with familial RCC. Potential tumour suppressor
genes of this area are FHIT, LSAMP, NORE1, and FBXW7 [53].
The tuberous sclerosis complex (TSC) is associated with
inactivating mutations of TSC1 at 9q34 (hamartin) or of TSC2
at 16p13.3 (tuberin). TSC1 and TSC2 inhibit mTOR, and
therefore these patients show an increased risk for RCCs
[53,54].
Other frequently mutated genes in RCC are RAS, BRAF,
p53, pRB (retinoblastoma), cyclin-dependent kinase inhibitor 2A (CDKN2A), PTEN, and ERBB2 [53,55]. Further frequent
alterations are found at chromosomes 5q, 7, 1p, 4, 9, 13q,
and 14q [53,56].
5.8.
Epigenetic alterations in renal cell carcinoma
5.8.1.
DNA hypermethylation
DNA hypermethylation around the promoter regions
silences tumour suppressor genes and therefore plays an
important role in carcinogenesis and tumour progression.
The number of candidate genes silenced by DNA hypermethylation in RCC is rising [53]. Data suggest that
the average number of methylated genes is higher in VHL
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EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 52–59
wild-type tumours than in VHL-mutated tumours. The Ras
association domain family member 1 (RASSF1), twist
homolog 1 (TWIST1), cadherin 13 (CDH13), matrix metalloproteinase 2 (MMP2), and tumour suppressor candidate 3
(TUSC3) are frequently methylated in sporadic RCC with
wild-type VHL. Proapoptotic genes are also often hypermethylated (eg, APAF1 and DAPK1) [53,57]. Wnt antagonists
(SFPR1/2/5, WIF1, and DKK3) frequently show hypermethylation [58,59]. Other candidate genes are UCHL-1, TGFBR3,
GATA3, TIMP3, FHIT, BIK, TU3A. and XAF1 [53].
5.8.2.
Histone modifications
The role of histone modifications in RCC remains unclear.
The levels of H3K4 methylation seem to be associated with
the prognosis of RCCs as well as the role of H3K27 as
previously reported [60,61]. Further mutations in the
histone methyltransferase and demethylase encoding genes
were described in RCC [53,55].
6.
Table 2 – Potential future marker profile for renal cell carcinomas*
Hypoxia inducible
Cell-cycle regulation
Miscellaneous
p53
Bcl-2
PTEN
Cyclin A
P27
Gelsolin
Vimentin
Ca 125
CD44
Androgen receptors
Caveolin-1
VEGFR
Metastatic pattern
Survivin
PAX 8
Topoisomerase II a
CP
CD 95 (Fas/APO 1)
SAA
CA IX
CA XII
CXCR4
VEGF
IGF-1
Proliferation
Ki-67
Anillin
GST
Cell adhesion
EpCAM
EMA
E-cadherin
X-catenin
Cadherin-6
PTEN = phosphatase and tensin homologue; VEGF = vascular endothelial
growth factor; IFG = insulinlike growth factor; GST = glutathione-S-transferase.
*
Modified according to references Jones et al. [65], Maruschke et al. [68], Lam
et al. [71], and Eichelberg [72].
Individualised molecular approach
The molecular characterisation of individual RCC may
potentially be useful for the better individual assessment
of prognosis, and the identification of biomarkers and
targets of specific treatments may eventually help improve
treatment. Despite advances in targeted therapies that
allow a prolongation of overall survival in patients with
metastatic disease, improvements in individualised diagnosis and prognosis would be desirable [62–64].
Nevertheless, considerable progress has been made in
the understanding and characterisation of metastatic
disease progression, especially in ccRCC, by microarray
expression profiling analyses [65–67]. However, currently
there are no biomarkers for established daily clinical use in
a diagnostic, prognostic, and/or predictive individualised
setting for RCC. In spite of everything, there are still a lot of
variations between the extensive published data and a lack
of consistency due to the technologies and experimental
set-ups associated with differences of the applied biostatistic analytic algorithms. The challenge of analysing the
molecular nature of RCC by gene expression profiling
consists of the meaningful analysis of the mass of data
obtained. At present, the problem seems no longer related
to obtaining gene expression profiles but to the interpretation of the results [68]. The creation of a useful and robust
workflow for standardising the statistical interpretation
provides an opportunity to reduce this problem. A
systematic approach such as warranted by the recently
described gene set enrichment analysis (GSEA) is clearly
needed to analyse raw data from microarray analyses in an
effective way with consideration to the complexity of
tumour biology [69,70]. GSEA provides numerous sets of
genes with similar function and affiliation to certain cellular
subunits or molecular pathways by integrating information
from manually accumulated databases with large-scale
expression data. However, several genes have been
repeatedly reported as deregulated in RCC but still with
considerable variation and a lack of consistency between
published data.
Conclusions
7.
Due to the complex processes of tumour development,
progression, and metastatic behaviour of RCC, it is not
feasible to get only a few established single biomarkers for
clinical application. Prospectively, there will rather be a
whole panel of genes generated with respect to the different
cellular functions and to the special indication in a predictive,
diagnostic, or therapeutic manner (Table 2) [71,72].
Conflicts of interest
The authors have nothing to disclose.
Funding support
None.
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