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Epigenetics and genetics in endometrial cancer: New carcinogenic

mechanisms and relationship with clinical practice

Article  in  Epigenomics · April 2012

DOI: 10.2217/epi.12.13 · Source: PubMed

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Epigenetics and genetics in endometrial cancer:

new carcinogenic mechanisms and relationship with
clinical practice
Endometrial cancer is the seventh most common cancer worldwide among females. An increased incidence
and a younger age of patients are also predicted to occur, and therefore elucidation of the pathological
mechanisms is important. However, several aspects of the mechanism of carcinogenesis in the endometrium
remain unclear. Associations with genetic mutations of cancer-related genes have been shown, but these
do not provide a complete explanation. Therefore, epigenetic mechanisms have been examined. Silencing
of genes by DNA hypermethylation, hereditary epimutation of DNA mismatch repair genes and regulation
of gene expression by miRNAs may underlie carcinogenesis in endometrial cancer. New therapies include
targeting epigenetic changes using histone deacetylase inhibitors. Some cases of endometrial cancer may
also be hereditary. Thus, patients with Lynch syndrome which is a hereditary disease, have a higher risk
for developing endometrial cancer than the general population. Identification of such disease-related
genes may contribute to early detection and prevention of endometrial cancer.

KEYWORDS: DNA hypermethylation n DNA mismatch repair n endometrial cancer
n epimutation n HDAC inhibitor n hMLH1 n lower uterine segment n Lynch syndrome
n miRNA n MMR
New carcinogenic mechanisms in
endometrial cancer
Endometrial cancer is the seventh most com-
mon cancer worldwide among females. In Japan,
the westernization of lifestyle has increased the
number of patients with endometrial cancer,
and this disease now accounts for approximately
40% of cancers of the uterus. A younger age of
onset is also predicted, and therefore it is impor-
tant to elucidate the pathogenesis of the cancer
and develop a treatment for it. However, beyond
the involvement of estrogen, the mechanism of
carcinogenesis in the endometrium remains
unclear. Advances in molecular biology of the
disease have revealed associations with varia-
tions and mutations of cancer-related genes, but
these do not provide a complete explanation for
endometrial carcinogenesis. Therefore, in recent
years, there has been a focus on epigenetic mech-
anisms, which involve the regulation of gene
expression by modulation of chromatin without
changes in DNA sequences. Breakdown of the
DNA mismatch repair (MMR) mechanism by
aberrant methylation is particularly important
for development of type 1 endometrial cancer,
and changes in expression of genes such as
hMLH1 and hMSH2 may be involved in this
mechanism. Epimutation, histone deacetylation
and hypermethylation may all be important epi-
genetic carcinogenic mechanisms in endome-
trial cancer, and regulation of gene expression
Kouji Banno*, Iori Kisu,
Megumi Yanokura,
Kenta Masuda,
Arisa Ueki,
by small noncoding RNAs, called miRNAs, Yusuke Kobayashi,
without a change in the methylation level of Nobuyuki Susumu
the gene itself has also been shown.
& Daisuke Aoki
Most cases of type I endometrial cancer
Department of Obstetrics &
result from the malignant transformation after Gynecology, School of Medicine,
changes from a normal endometrium to atypical Keio University, Shinanomachi 35
Shinjuku-ku, Tokyo 160–8582, Japan
endometrial hyperplasia, a precancerous lesion. *Author for correspondence:
This process is thought to be due to accumu- Tel.: +81 3 3353 1211
lation of mutations in cancer-related genes, Fax: +81 3 3226 1667
kbanno@sc.itc.keio.ac.jp
including oncogenes, tumor suppressor genes,
and DNA MMR genes. The cancer thus devel-
ops in a multistage process, which is referred
to as multistage carcinogenesis. By contrast, if
aberrant cancer-related genes are already present
in germ cells, the lifetime risk for endometrial
cancer increases, and approximately 5% of cases
of endometrial cancer are caused by a genetic
predisposition. Lynch syndrome (hereditary
nonpolyposis colorectal cancer), Cowden syn-
drome (CS) and Peutz–Jeghers syndrome (PJS)
are hereditary diseases with an increased risk
for endometrial cancer, with Lynch syndrome
being the most frequent disease associated with
hereditary endometrial cancer. Lynch syndrome
is also associated with the aberrant expression
of DNA MMR genes, while CS is linked to
the aberrant expression of PTEN. These results
are important in understanding the carcino-
genic mechanism and biological characteris-
tics involved in the development of sporadic
endometrial cancers. part of

10.2217/EPI.12.13 © 2012 Future Medicine Ltd Epigenomics (2012) 4(2), 147–162 ISSN 1750-1911 147
Review Banno, Kisu, Yanokura et al.

Cancer & epigenetics same DNA allows nucleosome formation and

Epigenetics refers to information other than the
DNA base sequence that is directly stored at the
time of somatic cell division. Epigenetic mecha-
nisms of regulation of gene expression include
DNA methylation, histone modification and
the effects of polycomb group proteins. In DNA
methylation in vertebrates, methyl groups are
added to cytosine bases at CpG sites (a cytosine
base followed by a guanine base in the DNA
sequence) by enzymatic transfer of the methyl
group from S-adenosyl-l-methionine by DNA
methyltransferases. There are two types of DNA
methylation: maintenance methylation and
de novo methylation. In maintenance methyla-
tion, the methylation pattern is maintained in a
new DNA strand at the same CpG as that in the
template DNA. Thus, in DNA replication asso-
ciated with cell division, the methylation pat-
tern in the template DNA is copied into a new
DNA to maintain the pattern in descendants.
By contrast, in de novo methylation, CpG sites
are newly methylated in differentiation, aging or
tumorigenesis. DNA methyltransferases, includ-
ing DNMT1, DNMT2, DNMT3A, DNMT3B
and DNMT3L, are divided into those associated
with maintenance methylation and those that
produce de novo methylation. DNA methylation
of CpG islands (regions with a high density of
CpG sites) in promoters upstream of the start
of gene transcription plays a critical role in gene
expression. When the DNA in this region is not
methylated, a nucleosome does not form and
transcription occurs, while methylation of the
Table 1. Highly methylated genes in endometrial cancer.
Gene Function Ref.
hMLH1 DNA mismatch repair
APC Wnt signaling molecule [3,10]
E‑cadherin Cell–cell adhesion
CHFR M phase checkpoint gene [3,11,12]
CASP8 Caspase
TGF‑bRII Action to INK4a genes
P73 p53 family
HOXA11 Proliferation and differentiation of human endometrium
COMT Estrogen-converting enzyme
Sprouty2 FGF and RAS-MAPK pathway inhibition
RASSF1A Gene suppressor gene for RAS-MAPK pathway
GPR54 Endogenous receptor of Kisspeptin, a suppressor of cancer [6]
metastasis
CDH1 Promotor of E‑cadherin
RSK4 Tumor suppressor gene targeting ERK signaling pathway
blocks transcription. Anticancer genes such as
hMLH1, CDKN2A and CDH1 (E‑cadherin) are
inactivated by DNA methylation of the promoter
of CpG islands, which suggests that aberrant
DNA methylation may cause carcinogenesis.
DNA hypermethylation in
endometrial cancer
Among the epigenetic mechanisms, DNA methy­
lation has been most widely studied. Altered
DNA methylation has been linked to tumorous
lesions [1,2] and hypermethylation is commonly
associated with the downregulation of gene
expression. Analysis of methylation in micro-
scopic amounts of DNA is possible at a high sen-
sitivity using the PCR. However, aberrant DNA
methylation also occurs in noncancerous cells
and attention should be paid to whether truly
cancer-specific DNA methylation is detected.
Some studies have tried to detect methylation
of genes specific to particular cancers for diag-
nosis. In cancer screening, genes with aberrant
methylation are detected in clinical specimens
mixed with normal cells. Methylation-specific
PCR, in which bisulfite treatment and PCR
are combined, can be used to detect aberrantly
methylated genes with high accuracy from a
small amount of DNA from cancer cells. In a
2009 review, Muraki et al. reported gene silenc-
ing due to hypermethylation of hMLH1 and
APC, E‑cadherin, CHFR, CASP8, TGF‑bRII,
p73, HOXA11 and COMT in endometrial cancer
[3] . Since this review, further studies have shown
hypermethylation of gene promoters linked to
reduced expression of SPRY2 [4] , RASSF1A [5] ,
GPR54 [6] , CDH1 [7] and RSK4 [8] through a
[3] similar silencing mechanism (Table 1) . Among
these genes, aberrant methylation is detected
most frequently in hMLH1 in endometrial can-
[3] cer and is considered to be an important event
in the early stage of endometrial carcinogenesis;
[3]
however, the mechanism of aberrant methyla-
tion remains unclear. hMLH1 encodes the DNA
[3]
MMR protein and it has been proposed that a
[3] cascade of malignant transformation occurs in
[3] which microsatellite instability (MSI) induced
[3]
by the downregulation of hMLH1 due to aber-
rant methylation induces mutations in hMSH6
[4]
and other cancer-related genes such as TGF‑bII,
[5] BAX and PTEN [9] .
Hypermethylation of the APC promoter is
not found in the normal endometrium or in
[7] endometrial hyperplasia, but is detected in atypi-
cal hyperplasia and early endometrial cancer.
[8]
Interestingly, the frequency of hypermethylation

148 Epigenomics (2012) 4(2) future science group


in the APC promoter is reduced with progression
of endometrial cancer, which led Ignatov et al.
to suggest that this hypermethylation may be an
important event in early malignant transforma-
tion of the endometrium [10] . Satoh et al. linked
hypermethylation to the response of tumors to
taxane drugs [11] and Wang et al. found that
reduced expression of CHFR by hypermethyla-
tion improves the response of both stomach and
endometrial cancers to paclitaxel [12] . SPRY2
is an antagonist regulator of receptor tyrosine
kinases in the FGF and RAS‑MAPK pathways
and a tumor suppressor gene involved in cell
proliferation, differentiation and angiogenesis.
Parts of the FGF and RAS‑MAPK pathways are
changed in endometrial cancer and expression
of SPRY2 is reduced due to hypermethylation
in several types of cancer [13–15] . Velasco et al.
found that SPRY2 in the normal endometrium
is expressed in accord with the menstrual cycle
and suggested that SPRY2 contributes to growth
of glandular structures. Furthermore, SPRY2
expression is extremely low in advanced inva-
sive cancers and other types of endometrial can-
cer, other than endometrioid adenocarcinoma,
which indicates that SPRY2 may play a role in
suppression of endometrial cancer by regulating
the MAPK pathway [4] .
RASSF1A is a tumor suppressor that is a
negative regulator in the RAS‑MAPK pathway
and, along with SPRY2, has reduced expression
in various cancers. In a comparison of normal
and cancerous endometrial tissues, Pallares
et al. showed that the RASSF1A promoter was
hypermethylated and that reduced expression of
RASSF1A was prevalent in endometrial cancer
with MSI, especially in advanced cancers. This
led to the suggestion that RASSF1A participates
in cell proliferation and apoptosis by regulating
the MAPK pathway, and has effects on malig-
nant transformation of the endometrium [5] .
GPR54 is an endogenous receptor of kiss­peptin
(KISS1), a suppressor of cancer metastasis, and
has reduced expression in some cancers, but
an unclear status in endometrial cancer. Kang
et al. found high survival rates in cases with high
GPR54 expression and showed that expression
of GPR54 is epigenetically regulated. Functional
recovery of GPR54 was possible with treatment
with 5-aza-2-deoxycytidine (5‑aza‑dC), a drug
that causes DNA hypomethylation, and sub-
sequent expression of GPR54 and activation
of a downstream response pathway involv-
ing m ­ etastin-10 were effective for inhibiting
metastasis of endometrial cancer [6] . CDH1 is
a promoter of E‑cadherin. Yi et al. found that
future science group
Epigenetics & genetics in endometrial cancer Review
hypermethylation of CDH1 reduced E‑cadherin
expression in endometrial cancer, with resulting
effects on clinical and pathological progression
and 5‑year survival rates. Hypermethylation of
CDH1 is common in undifferentiated cancers,
leading to the suggestion that this mechanism
may be more closely associated with carcino-
genesis than invasive capacity [7] . RSK4 is a
substrate of ERK that inhibits transcriptional
activity of some receptor tyrosine kinases for
certain targets. RSK4 is also associated with the
FGFR2/RAS/ERK signaling pathway and is a
tumor suppressor. Dewdney et al. showed that
expression of RSK4 is reduced by hypermethyla-
tion in colon, breast and kidney cancer, as well as
in endometrial cancer, but the tumor inhibitory
action of RSK4 in the endometrium is currently
unclear [8] .
Epimutation & malignant
transformation of the endometrium
Epimutation is a term that refers to the epi­
genetic silencing of a gene for which expression is
normally not suppressed, or epigenetic activation
of a gene for which expression is normally sup-
pressed [16,17] . Many studies of malignant trans-
formation of the endometrium and epimutation
of genes have been conducted and have mainly
focused on three genes: hMLH1, hMSH2 and
EPCAM. hMLH1 is a DNA MMR gene. MMR
deficiency is especially prevalent in endometrial
cancer and is found in approximately 20–30%
of cases. hMSH2, hMSH6 and PMS2 are also
DNA MMR genes and hMLH1 and hMSH2
are thought to be involved in endometrial can-
cer, similarly to colon cancer [18] . Since Kondo
et al. first showed that epigenetic inhibition of
hMLH1 expression is more frequent than that of
hMSH2 in endometrial cancer [19] , most studies
have examined hMLH1 and this gene has been
found to be a tumor suppressor that has reduced
expression in various cancers.
In endometrial cancer, inactivation by
methylation of hMLH1 is found in approxi-
mately 30% of cases. Inactivation of hMLH1
is thought to be an important step in the early
stage of malignant transformation of the uterus.
Banno et al. detected aberrant methylation of
hMLH1 in 40.4% of cases of endometrial can-
cer, and similar aberrant methylation of APC,
E‑cadherin and CHFR in 22.0, 14.0 and 12.8%,
respectively. In cases with aberrant methylation
of hMLH1 and E‑cadherin, protein expression
was significantly reduced (hMLH1: p < 0.01,
E‑cadherin: p < 0.05) [20] . Aberrant methylation
of hMLH1 was also detected in 14.3% of cases
www.futuremedicine.com 149
Review Banno, Kisu, Yanokura et al.
of atypical endometrial hyperplasia. However,
in the normal endometrium, none of the four
cancer-related genes were aberrantly methylated.
On the other hand, mutation of hMLH1 is espe-
cially common in cases with multiple primary
cancers such as Lynch syndrome (hereditary
nonpolyposis colorectal cancer) and epimutation
of the germline may be present even if mutation
of hMLH1 itself does not occur [21] . Hitchins
et al. suggested that epimutation may be inher-
ited through the mother, even though germline
epimutation is thought not to be inherited, and
found that during egg formation an epigenetic
error is essentially solved by demethylation,
but methylation may remain in a few cases.
However, this type of heredity epimutation
occurs with lower frequency than that of germ-
line sequence variants [22] . Goel et al. showed
that epimutation of hMLH1 could occur in the
allele from the father, in contrast to the under-
standing that epimutation of hMLH1 occurred
only in the allele derived from the mother [23] .
In two cases in which epimutation of hMLH1
occurred de novo, the allele was derived from the
father, rather than the mother, in one of the cases
[23] . These cases suggest that a new epimutation
may occur after fertilization, rather than during
egg formation without d­emethylation, and that
the epimutation can be inherited.
An inherited germline epimutation of hMSH2
was reported in 2006 by Chan et al. [24] in a
family line of three patients (brothers and sisters)
with colon or endometrial cancer with onset at
an early age. Genetic mutation of hMSH2 was
not present, but protein deficiency was recog-
nized and MSI was shown, with epimutation of
hMSH2 inherited from the mother. The same
epimutation was inherited by three children of
the three patients, indicating that not only a
DNA sequence mutation but also an epimuta-
tion can be inherited over multiple generations.
Sequencing shows that the epimutation does not
occur in all cells and that methylation mosaics
exist. Different degrees of methylation occur
based on the two-hit theory and may be a cause
of heritability of diseases.
The EPCAM gene codes for an epithelial cell
adhesion molecule and is overexpressed in most
cancers. There is a diversity of opinion on the
effects of EPCAM on carcinogenesis. EPCAM
is a homophilic intercellular adhesion molecule
that may prevent metastasis, but conversely may
also promote metastasis of cancers by preventing
intercellular adhesion mediated by E‑cadherin
[25] . In endometrial cancer, EPCAM deficiency
is also involved in hypermethylation of the
150 Epigenomics (2012) 4(2)
hMSH2 promoter [26] . Ligtenberg et al. showed
that epimutation of EPCAM itself is not involved
in development of endometrial cancer, but a
mutation to the 3´ side of EPCAM upstream and
close to hMSH2 epigenetically silences hMSH2,
l­eading to occurrence of endometrial cancer [26] .
Endometrial cancer & aberrant
methylation of miRNAs
miRNAs are short noncoding RNAs of approxi-
mately 18–25 bases that regulate expression of
genes. miRNAs have been found to be down-
regulated by methylation of DNA in various
cancers, and these miRNAs are referred to as
t umor-suppressor miRNAs (TS-miRNAs)
­
[27,28] . Identified TS-miRNAs include miR‑124,
miR‑126, miR‑137 and miR‑491 [27–31] .
Using a microarray assay, Huang et al. found
that SOX4 genes were highly expressed in
endometrial cancer cells. In database ana­lysis,
SOX4 was identified as a target for miR‑129­-2,
and a reporter assay showed that miR‑129-2
was a negative regulator of SOX4. Expression of
miR‑129-2 was verified in 117 cases of endome-
trial cancer with increased expression of SOX4,
and in 68% of the patients SOX4 expression
was silenced by methylation. Histone acetyla-
tion and DNA demethylation increased the
expression of miR‑129-2, reduced SOX4 expres-
sion, and suppressed proliferation of cancer
cells. Furthermore, hypermethylation of the
miR‑129-2 gene was statistically related to MSI
and the methylation status of hMLH1. Thus,
previously it was thought that a cancer gene
could only be activated by hypo­methylation of
a promoter, but this study proved that hyper­
methylation of a promoter can also directly
­activate a cancer gene [32] .
Expression of miR‑152 is also inhibited by
DNA hypermethylation [33] . Tsuruta et al. iden-
tified miR‑152 as a candidate TS-miRNA in
endometrial cancer through DNA methylation
screening and expression screening of endome-
trial cancer cells. Methylation of miR‑152 is
altered in acute lymphocytic leukemia and
miR‑152 expression is changed in digestive sys-
tem cancers and cholangiocellular cancer [34–36] .
Tsuruta et al. found a high frequency of methyla-
tion and downregulation of miR‑152 and showed
that expression of miR‑152 can be recovered
by 5‑aza‑dC. Methylation of miR‑152 is com-
pletely consistent with expression, and hyper­
methylation in the promoter region of miR‑152
reduces expression. DNMT1 is a well-known tar-
get of miR‑152, and E2F3, MET and Rictor have
been identified as additional targets by Tsuruta
future science group

et al. [33] E2F3 is an E2F family transcriptional
inhibitor and may be a cancer gene [37] . MET
is a cell surface receptor for hepatocyte growth
factor and a known cancer gene [38] . Rictor is a
component of mTORC2 (mTOR complex 2),
which directly regulates phosphorylation of Akt
and is important in cancer cells [39,40] . Activation
of mTORC2-Akt signaling contributes to malig-
nant transformation of the endometrium, but
the action of Rictor in carcinogenesis is unclear.
However, silencing of miR‑152 appears to lead to
activation of multiple targets, and miR‑152 itself
and E2F3, MET and Rictor may be new targets
for treatment of endometrial cancer [33] .
Application of aberrant DNA
methylation in treatment of
endometrial cancer
Epigenetic patterns in cancers can be restored or
partially improved by pharmacological action,
unlike irreversible genetic changes. Anticancer
agents can produce epigenetic changes and
recovery of expression of inactivated cancer-
related genes due to methylation has been
attempted using methylation inhibitors. Lubbert
et al. obtained a response rate of 60% using
5‑aza‑dC in patients with myelodysplastic syn-
drome (MDS) [41] . In cases that were respon-
sive to 5‑aza‑dC, expression of p15INK4A was
detected following demethylation. Issa et al. also
obtained a response rate of 60% with repeated
administration of a low dose of 5‑aza‑dC in cases
of acute myelocytic leukemia [42] . However, a
problem with this approach is that demethyla-
tion is not sequence specific and removal of bio-
logically important methyl groups or activation
of oncogenes that are inactivated by methylation
may occur. Therefore, demethylating agents are
being developed that can, for example, demeth-
ylate a DNA sequence bound by a particular
transcription factor.
Utilization of epigenetic aberrations as mark-
ers of sensitivity to anticancer drugs is also being
examined. Satoh et al. found that aberrant meth-
ylation of CHFR, an M phase checkpoint gene,
is correlated with the sensitivity of tumors to
microtubule inhibitors [43] . This finding sug-
gests that treatment may be selected based on the
specific methylation properties of tumor cells.
CHFR is likely to be a marker for the response of
endometrial cancer to anticancer drugs. CHFR
includes a fork-head associated domain and a
RING finger domain, and was first identified
as a homolog of the yeast DMA1 gene [44] . If
mitotic stress occurs during M phase, CHFR
delays the progress from early to late prophase.
future science group
Epigenetics & genetics in endometrial cancer Review
CHFR is also an ubiquitin ligase with substrates
including Aurora‑A and polo-like-kinase 1.
When microtubule stress occurs, CHFR is
activated, decomposes Aurora‑A and polo-like-
kinase 1, and arrests the cell cycle [45,46] . The
fork-head associated domain may be associated
with phosphorylated proteins and is important
for checkpoint control, but further ana­lysis is
required to establish the molecules that interact
with CHFR.
CHFR is methylated at high rates in cancer
[43] and this has been proposed to have the fol-
lowing relationship with the mitotic index. In
normally functioning cells without detectable
CHFR methylation, cell division is stopped in the
G2/M phases by administration of docetaxel, an
anticancer agent, and the mitotic index is low. By
contrast, in cells in which expression of CHFR
is reduced by methylation, a high mitotic index
is found after administration of docetaxel; thus,
the expression level of CHFR and the mitotic
index are inversely correlated [47] . In some cells,
the checkpoint mechanism of action in response
to mitotic stress involves transition of cyclin B1
to the nucleus, which is unaffected by CHFR
methylation. In addition, if cells in which CHFR
is methylated are treated with 5‑aza‑dC, a meth-
ylation inhibitor, the checkpoint mechanism
is restored and the mitotic index is reduced.
Methylation of CHFR and sensitivity to micro-
tubule inhibitors (taxanes) are promising mark-
ers in endometrial cancer and in stomach and
cervical cancer, and the methylation index may
become a useful marker for prediction of the
effects of anticancer drugs [48,49] .
Histone deacetylase & histone
deacetylase inhibitors in endometrial
cancer
The nucleosome, a unit of chromatin, consists
of a core tetramer of histone pairs of H3–H4
dimers that form an octamer with two histone
H2A–H2B dimers, with approximately 147 bp
of DNA wrapping around the octamer about
1.75‑times. The crystal structure of the nucleo-
some shows that the N‑terminus of histones pro-
trudes to sites outside the DNA. The N‑terminal
domains of the histone core proteins (histone
tails) undergo post-translational modifications,
including acetylation, methylation, ubiquiti-
nation and phosphorylation. Combinations of
histone modifications define the status of acti-
vation of a chromosome, and therefore this is
considered to be a kind of genetic code. Histone
acetylation removes positive charges of lysine
residues and decreases electrostatic interactions
www.futuremedicine.com 151
Review Banno, Kisu, Yanokura et al.
with the negatively charged bases of DNA. This
reduces the affinity of the histone for the DNA
and leads to conversion of heterochromatin to
euchromatin, allowing cofactors to interact with
DNA and increase transcriptional activity.
Histone acetylation and deacetylation are
catalyzed by histone acetyl transferase and his-
tone deacetylase (HDAC) enzymes, respectively.
Histone acetylation activates binding of tran-
scription factors and enhances transcriptional
activation, while deacetylation inhibits transcrip-
tion. The 18 known HDACs are classified into
classes I–IV based on their amino acid sequence
homology at sites of enzyme activity [50,51] . Class I
enzymes (HDAC 1, 2, 3 and 8) are homologs
of yeast Rpd3 that are present mainly in nuclei
and are constitutively expressed in many cells
and tissues. Class II enzymes (HDAC 4, 5, 6,
7, 9 and 10) are homologs of yeast Hda1 and
are mainly present in the brain, myocardium
and skeletal muscles. Class II is further classi-
fied into classes IIa (HDAC 4, 5, 7 and 9) and
IIb (HDAC 6 and 10). Class III enzymes are
Sir2 homologs and include SIRT 1, 2, 3, 4, 5,
6 and 7. Class IV currently includes HDAC11
alone. The relationship between HDAC expres-
sion and endometrial malignant transformation
remains unclear. Class I HDAC expression in
the endometrium and in endometrial cancer
has recently been shown for the first time [52,53] .
HDAC expression occurs throughout the men-
strual cycle, but HDAC3 expression decreases
from menstrual days 6–10, suggesting that
HDAC expression is involved in endometrial dif-
ferentiation [52] . Endometrial cancer with strong
class I HDAC expression may have a poor prog-
nosis [53] and it is of note that many studies have
shown antitumor effects of HDAC ­inhibitors on
cancer, including e­ ndometrial cancer.
Table 2. Effect of histone deacetylase inhibitors in endometrial
cancer cells.
Group Substance HDAC inhibited ED50 (M) Ref.
Hydroxamate TSA Class I, II 5.2 × 10 -8
[59,60]
SAHA Class I, II, IV 7.8–31.0 × 10 -7 [61–63]
CBHA Class I 1.8–2.5 × 10 -6
Scriptaid Class I 9.0 × 10 -6
Oxamflatin Class I 2.5 × 10 -7
Short-chain fatty acid NaB Class I, IIa 8.3 × 10 -4
Valproate Class I, IIa 4.1 × 10 -4
Benzamides MS‑275 Class I, II 5.0–22.0 × 10 -7
M344 Class I, II 2.3 × 10 -6
Cyclic tetrapeptides Apicidin Class I, II 1.0 × 10 -6
CBHA: m‑carboxycinnamic acid bishydroxamic; ED50 : 50% effective dose; HDAC: Histone
deacetylase; NaB: Sodium butyrate; SAHA: Suberoylanilide hydroxamic acid; TSA: Trichostatin A.
152 Epigenomics (2012) 4(2)
HDAC inhibitors elevate acetylation of his-
tones and enhance transcriptional activity, lead-
ing to antitumor effects through induction of
apoptosis, cell cycle arrest, antiangiogenesis,
and cell differentiation. HDAC inhibitors can
increase expression of p21WAE1, which, along with
p27KIP1, is a cyclin-dependent kinase inhibitor
that decreases the kinase activity of the cyclin-
dependent kinase complex, leading to arrest of
the cell cycle in the G0/G1 phase [54] . HDAC
inhibitors elevate acetylation of histones in the
p21WAF1 promoter through selective inhibition of
particular HDACs, which restores production of
cyclin D1 and D2 and inhibits cell proliferation
[55] . Many basic studies have shown effects of
HDAC inhibitors on endometrial cancer cells.
HDAC inhibitors can also reduce bc1–2 expres-
sion, thereby blocking inhibition of apoptosis
in endometrial cancer cells, bind to b‑catenin,
and increase the expression of E‑cadherin, a
tumor suppressor gene. HDAC inhibitors can
also inhibit the expression of angiogenic growth
factors such as HIF‑1a, VEGF, VEGF receptor,
endothelial NO synthase, IL‑2 and IL‑8; induce
antiangiogenic factors such as p53 and the von
Hippel-Lindau tumor suppressor; and inhibit
angiogenesis [56] . As noted above, many tran-
scription factors and coregulators in transcrip-
tion are regulated by acetylation. Thus, HDAC
inhibitors can alter gene transcription by regulat-
ing the extent of acetylation of histones for tar-
get genes including ACTR, cMyb, E2F1, EKLF,
FEN, GATA, HNF‑4, HSP90, Ku70, NF‑kB,
PCNA, p53, RB, Runx, SF1, Sp3, STAT, TFIIE,
TCF 1 and YY1 [57] . A mechanism through
which HDAC inhibitors induce differentiation
in endometrial cancer cells via glycodelin has
also been described [58] .
Clinical studies of HDAC inhibitors are cur-
rently ongoing in solid cancers and hemato-
logic tumors. The inhibitors are classified into
hydroxamic acids, short-chain fatty acids, benza-
mides, cyclic tetrapeptides and sulfon­amide ani-
lides, based on their chemical structure. HDAC
inhibitors in clinical trials in endometrial can-
cer, the HDAC isoforms that are inhibited, and
[64] the preliminary results of the clinical trials are
[65]
shown in Table 2 . Trichostatin A (TSA) was iso-
[67]
lated from Actinomyces media as a differentia-
[66] tion-inducer for mouse erythroblastic leukemia
[63]
cells and was found to have HDAC inhibitory
[67] activity. In vitro, TSA has anti-tumor activity
[68] as an HDAC inhibitor and promotes cell dif-
[69] ferentiation. However, in vivo, the use of TSA
is restricted due to severe adverse reactions.
Dowdy et al. showed that TSA and paclitaxel
future science group

in combination inhibit the growth of Ark2 and
KLE endometrial cancer cells, with findings of
increased acetylation of tubulin and microtubule
stabilization [59,60] .
The most advanced HDAC inhibitor clini-
cally is suberoylanilide hydroxamic acid, which
is currently in Phase I and II clinical trials
[61,62] . In contrast to the adverse effects of TSA,
suberoylanilide hydroxamic acid has a high tol-
erability and good efficacy at a low dose, and
can be administered orally or intravenously [63] .
m‑carboxycinnamic acid bishydroxamic is a syn-
thetic HDAC inhibitor that inhibits cell prolif-
eration and induces cell differentiation in vitro at
micromolar concentrations. Takai et al. showed
that normal endometrial cells survived after
m‑carboxycinnamic acid bishydroxamic was
administered at a dose inhibiting proliferation
of endometrial cancer cells [64] . Scriptaid is a
HDAC inhibitor in the hydroxamic acid class
that targets the TGF‑b pathway, including
SMD4, and activates tumor suppressor genes
[65] . Sodium butyrate (NaB) is endogenous in
the human colon and may have efficacy in pre-
cancerous conditions and for tumorous lesions.
NaB was shown to be a HDAC inhibitor in vitro
in 1978, and Terao found that NaB inhibits
proliferation and promotes differentiation of
endometrial cancer cells. However, the half life
of NaB is only 5 min and the concentration rap-
idly decreases after intravenous administration;
therefore, a dose of 400 mg/kg/day is required
and clinical use is difficult [66] . Valproic acid
(VPA), a short-chain fatty acid, is an HDAC
inhibitor that is used for treatment of epilepsy
in clinical practice, and therefore many stud-
ies of VPA have been conducted. VPA is a safe
drug with less cell toxicity than HDAC inhibi-
tors such as TSA and has clinical potential due
to its long half-life [63] .
MS‑275 is a benzamide that induces expres-
sion of the cyclin-dependent kinase inhibi-
tor p21WAF1 and gelsolin, and regulates the cell
cycle. MS‑275 has anticancer effects in vivo and
in vitro, and clinical trials are ongoing in solid
cancers and hematologic tumors. Jiang et al.
showed that the number of Ark2 endometrial
cancer cells decreased by approximately 60%
after 4‑day administration of 0.5 µM MS‑275
[67] . M344 is a synthetic amide with a structure
similar to TSA. Jung et al. showed that M344
had activity as a HDAC inhibitor and promoted
cell differentiation [68] . Apicidin is a cyclic
tetrapeptide with antiprotozoal activity for api-
complexan parasites and has been shown to be
a HDAC inhibitor. Such cyclic tetrapeptides are
future science group
Epigenetics & genetics in endometrial cancer Review
classified into epoxyketones (e.g., HC‑toxin and
trapoxin) and nonepoxyketones (e.g., apicidin,
depsipeptide and FK228). Ueda et al. showed
that apicidin arrested the cell cycle and promoted
gene expression associated with apoptosis induc-
tion [69] . Oxamflatin is a sulfonamide derivative
that induces morphological recovery of K‑ras-
transformed NIH3T3 cells and of malignant
transformation induced by oncogenes such as
v‑src and v‑fos. Jiang et al. conducted a study of
oxamflatin in Ark2 endometrial cancer cells and
found that the tumor cells decreased by 78 and
95% at 4 days after treatment at doses of 0.25
and 0.75 µM, respectively. Thus, many HDAC
inhibitors have useful properties in vitro, but
their clinical application as anti-tumor agents
in endometrial cancer remains to be established.
Endometrial cancer as a
hereditary tumor
Tumors with aberrant accumulation within fam-
ilies and with a strong genetic background are
referred to as hereditary tumors. Most heredi-
tary tumors develop after a single gene associated
with cancer susceptibility undergoes a germline
mutation. Tumor genes, ­tumor-suppressor genes
and DNA MMR genes have been shown to
be disease-related genes in hereditary tumors.
Tumor genes are activated and result in malig-
nant transformation when one of a pair of genes
is mutated. By contrast, tumor suppressor genes
and DNA MMR genes result in malignant
transformation when both of a pair of genes are
inactivated. In hereditary tumors, a mutation of
either tumor suppressor gene may be inherited
from a parent; therefore, a tumor results due to
malignant transformation once the other allele
mutates. Some cases of endometrial cancer
develop due to hereditary predisposition, with
a high risk in several syndromes. Elucidation of
aberrant genes specific to these syndromes has
helped to clarify the carcinogenic mechanism of
hereditary endometrial cancer.
Endometrial cancer & Lynch
syndrome
Lynch syndrome is a typical familial tumor
with autosomal dominant inheritance. Female
patients with Lynch syndrome complicate with
endometrial cancer at a high incidence. In the
revised 1999 Amsterdam II Criteria (ACII)
endometrial cancer was included as a cancer sim-
ilar to colon, small intestine, ureteral and kid-
ney cancers (Box 1) [70] . The prevalence of Lynch
syndrome is 0.9–2.7% [71] , and approximately
2.3% of cases of endometrial cancer occur due
www.futuremedicine.com 153
Review Banno, Kisu, Yanokura et al.
to Lynch syndrome [72] . The lifetime risk of
endometrial cancer is 40–60% in females with
aberrant genes associated with Lynch syndrome
(Table 3) [73–75] .
Aberrant MMR genes are involved in carcino-
genesis of endometrial cancer. Cloning has been
performed in six MMR genes (MSH2, MLH1,
MLH3, MSH6, PMS1 and PMS2) and most
mutations occur in PMS2 and MSH2, in par-
ticular, and in MLH1 and MSH6 (Table 4) [76] .
In endometrial cancer, MSH2 and MSH6 are
strongly associated with carcinogenesis [77,78] .
If aberration occurs in these MMR genes, mis-
match bases cannot be correctly repaired, result-
ing in DNA strands of different length. This
phenomenon occurs in microsatellite regions of
the human genome and is referred to as MSI.
Most short-tandem repeats such as micro­
satellites exists in noncoding regions and have
no relation to production of aberrant proteins
with mutations. However, short-tandem repeats
can occur in regions coding genes for which
mutation is involved in carcinogenesis, includ-
ing BAX, which is related to apoptosis induction,
and IGF2R, which is associated with inhibition
of cell proliferation.
Broaddus et al. examined the clinico­
pathological characteristics of 50 patients with
Lynch syndrome-related endometrial cancer
(group A), 42 patients with sporadic endo­
metrial cancer who were aged <50 years old
and had no aberrant mutation (group B), and
26 patients with loss of MLH protein expression
and MSI-positive sporadic endometrial cancer
due to MLH promoter methylation (group C).
The mean ages in the three groups were 46.8,
39.9 and 61.1 years old, respectively, with a sig-
nificant difference between groups A and C.
There was slightly more frequent occurrence
of nonendometrioid adenocarcinoma (clear cell
adenocarcinoma, serous adenocarcinoma and
carcinosarcoma) in group A (14%). Regarding
differentiation, G2 and G3 cells were frequently
detected in group C and vascular invasion
Box 1. The Amsterdam II Criteria.
ƒƒ There should be at least three relatives with colorectal cancer or with an
hereditary nonpolyposis colorectal cancer-associated cancer: cancer of the
endometrium, small bowel, ureter or renal pelvis
ƒƒ One relative should be a first degree relative of the other two
ƒƒ At least two successive generations should be affected
ƒƒ At least one tumor should be diagnosed before the age of 50 years
ƒƒ Familial adenomatous polyposis should be excluded in the colorectal cancer
case if any
ƒƒ Tumors should be verified by histopathological examination
154 Epigenomics (2012) 4(2)
was also found in group C. Stage III and IV
advanced cancer was more common in groups B
and C compared with group A [79] . Thus, cases
of MSI-positive sporadic endometrial cancer due
to MLH1 promoter methylation had less differ-
entiation and most were advanced cancer; by
contrast, Lynch syndrome-related endometrial
cancer due to MLH1 or MSH2 gene mutation
was clinico­pathologically similar to endo­metrial
cancer with onset at an early age. However,
Lynch syndrome-related endometrial cancer had
a variety of histo­logical types, including nonen-
dometrioid adenocarcinoma, and had different
characteristics from sporadic endometrial can-
cer. In the study by Broaddus et al., most patients
with Lynch syndrome had a MSH2 mutation;
consequently, the clinicopathological character­
istics of patients with a MLH1 mutation is
unknown. The onset age of sporadic endome-
trial cancer was 60 years old, whereas that of
Lynch syndrome-related endometrial cancer was
only 48 years old [80] . However, the prognosis
of Lynch syndrome-related endometrial cancer
did not differ from that of sporadic endometrial
cancer [81] .
Hereditary endometrial cancer not
meeting the ACII
Definitive diagnosis of Lynch syndrome is per-
formed by a MMR genetic test in germ cells, but
ACII are used clinically. However, the results
of germline MMR gene mutations show that
some patients with a mutation do not meet ACII.
Hampel et al. conducted a genetic ana­lysis of
MMR in 543 patients with endometrial cancer
and detected a gene mutation in 10 (1.8%) of
these cases (one in MLH1, two in MSH2 and six
in MSH6 ), of which seven did not meet ACII
[82] . ACII does not include Lynch syndrome-
related cancers such as gastric, breast and ovar-
ian cancers, and therefore these criteria alone
cannot detect all cases of hereditary endometrial
cancer.
The Japanese working group on familial
endometrial cancer conducted a genetic ana­
lysis in patients who were suspected to have
Lynch syndrome, although they did not meet
ACII. Lynch syndrome-related tumors (colon,
endometrial, small intestinal, ureteral, renal
pelvic, gastric, breast and ovarian cancers) were
found in at least two families (including first-
degree relative probands). A genetic ana­lysis was
performed in 120 patients, including 57 with
endometrial cancer in whom the age of onset of
at least one tumor was ≤50 years old (group A),
48 with endometrial cancer and simultaneous
future science group
 Epigenetics & genetics in endometrial cancer Review
or metachronous complication with a Lynch Table 3. Risks of patients with hereditary diseases developing
syndrome-related tumor (group B), and 15 endometrial cancer throughout life.
with endometrial cancer who met the criteria
Disease Risk throughout life (%) Ref.
for groups A and B (group A + B). Peripheral
blood leukocyte-derived DNA was obtained Lynch syndrome 42 (diseased until 70 years old) [74]

and germline mutations in three MMR genes 61 (MSH2 mutation) [75]

42 (MLH1 mutation) [75]
(MLH1, MSH2 and MSH6 ) were analyzed by
direct sequence ana­lysis. Gene mutations were Cowden syndrome 5–10 [100]

found in 18 (15%) of the 120 patients: nine Peutz–Jeghers syndrome 9 [110]

(15.8%) in group A, four (8.3%) in group B,
and five (33.3%) in group A + B. Of 18 patients and colon cancers at <50 years old, those with
with genetic mutations, five (27.8%) had a endometrial and ovarian cancers who simulta-
mutation in MLH1, four (22.2%) in MSH2 neously or metachronously complicated with
and nine (50%) in MSH6. Of nine patients a Lynch syndrome-related tumor, those with
with a mutation in MSH6, eight had mutations endometrial and colon cancers with at least two
mainly in exons 4–6 and most were frameshift first- or second-degree relatives who developed
mutations. On the other hand, in patients Lynch syndrome-related tumor, and those with a
with double cancer who had genetic mutations first or second-degree relative who met the above
(group B: 4, group A + B: 5), five and one of criteria had more than a 5–10% probability of
six patients with double cancer including colon a hereditary predisposition for endometrial and
cancer had mutations in MLH1 and MSH2, colon cancers; therefore, making evaluation of
respectively. By contrast, all three patients with hereditary risks useful [85] .
double cancer including breast or ovarian can- MSI ana­lysis and immunohistochemical stain-
cer had mutations in MSH6. All of these dou- ing are useful in screening to identify subjects
ble cancers developed simultaneously with or for a mutation test for Lynch syndrome. The
before development of endometrial cancer [83,84] . NCI recommends five satellite markers (BAT25,
These results suggest that there may be many BAT26, D2S123, D5S346 and D173250) for
cases of Lynch syndrome-related endometrial MSI ana­lysis [86] . A case with an allelic shift in at
cancer and that genetic analyses for MMR least two markers is defined as MSI-high and that
genes are useful in patients with endometrial with only one marker as MSI-low. However, most
or double cancer showing a familial cluster of MSI reflects inactivity due to epigenetic changes
cancer. Furthermore, the MSH6 gene appears in MMR genes, and particularly MLH1 promoter
to be strongly associated with carcinogenesis of methylation, which occurs in sporadic endome-
endometrial cancer. trial cancer at a rate of approximately 20% [87] .
Therefore, the value of MSI as screening for
Screening & surveillance for Lynch Lynch syndrome is not always high in patients
syndrome-related endometrial with endometrial cancer. On the other hand,
cancer immunohistochemical staining may be effective
In general, hereditary tumors tend to have for identifying aberrant MMR genes [88] .
juvenile onset, multiple organ double cancer, Patients with Lynch syndrome and persons
and bilateral occurrence. The guidelines of the from a family with Lynch syndrome have a high
Society of Gynecologic Oncologists Education risk of other cancers, and therefore appropriate
Committee are useful for specific diagnosis of screening and preventive measures for cancer
Lynch syndrome [85] . These guidelines suggest are needed. Lindor et al. proposed screening for
that patients with endometrial and colon cancers
who meet ACII, those who simultaneously or Table 4. Mismatch repair genes related to Lynch syndrome.
metachronously develop endometrial and colon Gene Chromosomal cDNA size Number of Gene size
cancers at <50 years old, those who simultane- position (kb) exons (kb)
ously or metachronously develop ovarian and MSH2 2p21 2.8 16 73
colon cancers at <50 years old, and those with
MLH1 3p21–p23 2.3 19 58–100
a first- or second-degree relative with aber-
rant MMR genes have a 20–25% probability MLH3 14q24.3 4.3 12 37
for a hereditary predisposition to endometrial MSH6 2p21 4.2 10 20
and colon cancers. Therefore, hereditary risks PMS1 2q31 2.8 12 93
should be evaluated in these patients. It has been
shown that patients diagnosed with endometrial PMS2 7q22 2.6 15 16

future science group www.futuremedicine.com 155

Review Banno, Kisu, Yanokura et al.
females with Lynch syndrome using colonos-
copy (once every 1–2 years from 20–25 years
old), endometrial sampling (once a year from
30–35 years old), transvaginal ultrasonography
(once a year from 30–35 years old), urine cytol-
ogy (once every 1–2 years from 25–35 years old),
and history taking and physical examination
including genetic counseling and review (every
year from 21 years old), with hysterectomy plus
adnexectomy to be considered if a patient does
not want a child [89] . However, the effective-
ness of these surveillance methods remains
unclear [90] .
Carcinoma of the lower uterine
segment & Lynch syndrome
Endometrial cancer that occurs in the lower
uterine body is referred to as carcinoma of the
lower uterine segment (LUS) and has recently
been shown to be a hereditary cancer [91] .
Carcinoma of the LUS accounts for 3–8% of
cases of endometrial cancer [92–94] ; however, it
has characteristics of advanced muscle invasion
and juvenile onset in comparison with non-LUS
carcinoma [92,93,95] . Westin et al. conducted a
large-scale comparative study in 35 patients
with carcinoma of the LUS and 974 with non-
LUS carcinoma. The mean ages were 54.2 and
62.9 years old in the LUS and non-LUS cases,
respectively, with a significant difference in
the age of onset. The younger age of onset of
carcinoma of the LUS was suggested to indi-
cate a hereditary predisposition. Five of the
35 patients with carcinoma of the LUS (14.2%)
met the ACII criteria. All of these patients had
a MSH2 mutation, were highly MSI-positive,
and showed loss of MSH2 and MSH6 proteins.
Four patients (11.4%) did not meet ACII, but
had loss of MSH2 and MSH6 proteins, and
one patient (2.8%) did not meet ACII, but had
loss of MSH2 and MSH6 proteins. Based on
these results, ten (29%) of the 35 patients were
concluded to have carcinoma of the LUS associ-
ated with Lynch syndrome. In comparison with
the approximately 2.3% incidence of Lynch syn-
drome in all cases of endometrial cancer [72] , the
incidence of Lynch syndrome in cases of carci-
noma of the LUS was extremely high, which sug-
gests that carcinoma of the LUS is a characteris-
tic phenotype of endometrial cancer that occurs
in patients with Lynch syndrome. Westin et al.
suggested that the sensitivity to DNA MMR was
high due to specificity of the endometrial duct
and interstitium in the LUS, but the reason why
Lynch syndrome is associated with carcinoma of
the LUS remains unclear [93,96] .
156 Epigenomics (2012) 4(2)
Endometrial cancer & CS
CS is a rare disease with autosomal dominant
inheritance and has characteristics of multiple
hamartomas that occur in various tissues. The
prevalence of CS is estimated to be one per
200,000–250,000 population [97] . Patients with
CS have increased risks for malignant tumors,
and particularly breast, thyroid and endome-
trial cancers. Onset of CS is thought to involve
PTEN [98] and approximately 80% of patients
with CS have a PTEN mutation [99] . The life-
time risk for endometrial cancer is 5–10% in
patients with CS [100] , compared with 2–4% in
the general population (Table 3) . PTEN codes for
a protein with tyrosine kinase activity and acts
as a tumor suppressor gene. PTEN is also a phos-
phatidylinositol phosphatase that regulates PI3K
activity and inhibits activation of Akt via PI3K.
Akt is a serine/threonine kinase that activates
or inactivates downstream factors by phosphor-
ylating serine/threonine residues, with resulting
transmission of signals related to cell growth,
survival, differentiation and glucose metabo-
lism [101] . Akt is related to cell survival through
inactivation of proapoptotic executioner caspases
and transcription factors related to apoptosis-
inducing factors. Therefore, if PTEN regulation
of Akt activation is lost, the PI3K‑Akt pathway is
activated and leads to malignant transformation
of endometrial cells [102,103] . Screening criteria
for endometrial cancer in patients with CS are
still under discussion [104–106] . In this context,
it is of note that a recent study showed a rela-
tionship of adolescent-onset endometrial cancer
with CS [107] .
Endometrial cancer & PJS
PJS is characterized by multiple hamartomatous
polyps in the gastrointestinal tract and muco-
cutaneous pigmentation. Patients with PJS
have a higher risk of developing a malignant
tumor in the gastrointestinal tract and other
organs compared with the general population.
LKB1/STK11 has been identified as a disease-
related gene with autosomal dominant inher-
itance, and a LKB1 gene mutation is found in
80–94% of patients with PJS [108] . The incidence
of PJS is estimated to be one per 50,000–250,000
population [109] . Patients with PJS are at risk for
gynecological cancers and have a 9% lifetime
risk of developing endometrial cancer [110] . LKB1
codes for a serine/threonine kinase and has
functions including regulation of glucose, lipid
metabolism, cell proliferation and cell polarity.
A relationship of LKB1 downregulation with
endometrial carcinogenesis has been found using
future science group

knockout mice, with the suggestion that LKB1
inactivation correlates with endometrial malig-
nant pheno­t ypes and that LKB1 downregulation
may be a prognostic factor in endometrial cancer
[111] . Screening for endometrial cancer similar
to that used in Lynch syndrome can be used
in patients with PJS; however, it has been sug-
gested that specific surveillance is unnecessary
based on the relatively low risk of development
of endometrial cancer (Table 3) [110] . Cases of mul-
tiple cancer including endometrial cancer have
also been reported in patients with PJS [112] .
Conclusion & future perspective
In 2007, endometrial cancer was newly diag-
nosed in 226,000 women worldwide. It is the
cause of death of more than 7000 people annu-
ally in the USA alone. In Japan, the number
of patients with this cancer is increasing and
a younger age of onset is also predicted, which
emphasizes the need to find more effective
therapies based on improved understanding of
the pathogenesis. As for many other cancers,
development of endometrial cancer cannot
be fully explained by genetic mutations alone
and is likely to involve epigenetic changes. In
endometrial cancer, mutations of MMR genes
are important and regulation of these genes has
been widely examined. Expression of hMLH1,
hMSH2 and EPCAM is suppressed by pro-
moter hypermethylation, which inhibits direct
or indirect DNA MMR and contributes to
development of endometrial cancer type 1 and
development of endometrial cancer in Lynch
syndrome. Reduced expression of genes such
as APC, E‑cadherin, CHFR, SPRY2, RASSF1A,
GPR54, CDH1 and RSK4 through a similar
mechanism of hypermethylation has also been
found in endometrial cancer. Suppression
of gene expression by miRNAs also occurs
in endometrial cancer and expression of the
miRNA itself may be increased or decreased
by promoter methylation, based on differ-
ences between normal and cancerous endo­
metrial tissue, and may contribute to malignant
­transformation of the endometrium.
More knowledge of the mechanism of malig-
nant transformation of the endometrium is likely
to reveal new therapeutic targets and lead to the
discovery of new drugs. This is especially true
for miRNA targeting, since siRNA modulation
of miRNAs has been established in vitro and
a similar approach in vivo may prevent pro-
gression of carcinogenesis caused by silencing
of miRNA. Drugs that cause gene demethyla-
tion (DNA methyltransferase inhibitors) have
future science group
Epigenetics & genetics in endometrial cancer Review
also been developed, but are not used in clini-
cal practice due to cell toxicity. Many HDAC
inhibitors (i.e., anticancer agents targeting aber-
rant acetylation) have also been developed and
improved drugs with focused targeting may be
useful in clinical practice.
Lynch syndrome, CS and PJS are hereditary
diseases associated with endometrial cancer, and
Lynch syndrome is particularly important with
regard to the prevalence and risk for develop-
ing endometrial cancer. In most patients with
Lynch syndrome, endometrial cancer is likely
to be a sentinel cancer; therefore, it is impor-
tant to suspect Lynch syndrome if juvenile
endometrial cancer is diagnosed. ACII crite-
ria are used for diagnosis of Lynch syndrome,
but genetic ana­lysis should also be performed
in high-risk patients with familial accumula-
tion, even though they do not meet diagnos-
tic criteria. For patients with a hereditary pre­
disposition, screening and preventive measures
are recommended, but their efficacy is currently
unknown. Screening for endometrial cancer
will also be important in patients with CS and
PJS, but the risk for developing endometrial
cancer is lower than that in Lynch syndrome.
Investigation of the extent to which survival is
improved by current screening and preventive
measures and establishment of new diagnostic
criteria and screening methods are required. A
relationship with disease-related genes in carci-
noma of the LUS and Lynch syndrome has been
suggested. Clarification of this relationship and
discovery of factors associated with the onset
of hereditary endometrial cancer will require
large-scale global studies.
Next-generation sequencing has provided
genome-wide analyses of genetics and epi­
genetics, and consequently, genome-wide
association studies have attracted attention.
Genome-wide analyses of lung cancer and
melanoma [113,114] have identified mutations
in at least 10,000 somatic cells and it is likely
that dozens of missense mutations are present
in protein-coding genes. Genome-wide com-
parison has shown that mutation from guanine
to thymine is common in pulmonary adeno-
carcinoma, whereas mutation from cytosine
to thymine is significantly more frequent in
melanoma. Genome-wide analyses are pro-
moting development of catalogs of genomic
aberrations in all cancers, and large-scale can-
cer genome projects including The Cancer
Genome Atlas (TCGA [201]) in the USA and
the International Cancer Genome Consortium
[202] , including research groups from 11 nations,
www.futuremedicine.com 157
Review Banno, Kisu, Yanokura et al.

have been started [115–117] . TCGA started with
studies in lung and ovarian cancer and glio­
blastoma, and analyses are currently ongoing in
at least 20 kinds of cancer, including endome-
trial cancer. However, a genome-wide study
of methylation in endometrial cancer has not
yet been performed, excluding one study that
used an array-based approach [118] . However,
data from 373 genome-wide studies of methyla-
tion in endometrial cancer are currently reg-
istered in TCGA and this number continues
to increase. Thus, genome-wide gene mutation
and methylation analyses are likely to produce
further breakthroughs in understanding of the
­carcinogenic mechanism of ­endometrial cancer.
Financial & competing interests disclosure
The authors gratefully acknowledge grant support from the
Japan Society for the Promotion of Science (JSPS) through
a Grant-in-Aid for Scientific Research (KAKENHI); a
Grant-in-Aid for Scientific Research (C) (22591866) and
a Grant-in-Aid for Young Scientists (B) (21791573); the
Ichiro Kanehara Foundation; and the Keio University
Medical Science Fund through a Research Grant for Life
Sciences and Medicine. The authors have no other relevant
affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict
with the subject matter or materials d­ iscussed in the
­manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.

Executive summary
Carcinogenic mechanism in endometrial cancer
ƒƒ Endometrial cancer is the seventh most common cancer worldwide among females and accounts for approximately 40% of cancers of
the uterus in Japan.
ƒƒ In addition to the involvement of hormones such as estrogen, epigenetic and genetic aberrations are important for carcinogenesis of
type I endometrial cancer.
Epigenetics in endometrial cancer
ƒƒ hMLH1, APC, E‑cadherin, CHFR, SPRY2, RASSF1A, GPR54, CDH1 and RSK4 are genes that are hypermethylated in endometrial cancer.
Aberrant promoter methylation of hMLH1 occurs in approximately 40% of cases and is an early-stage event in the malignant
transformation of the endometrium.
ƒƒ Epimutation of DNA mismatch repair genes hMLH1 and hMSH2 is a new mechanism of carcinogenesis in endometrial cancer.
ƒƒ miR‑152 is a tumor suppressor-type miRNA that shows decreased expression due to aberrant methylation in endometrial cancer. This
miRNA inhibits cell proliferation of endometrial cancer in vivo and in vitro.
ƒƒ Aberrant methylation of CHFR is a potential biomarker for sensitivity of endometrial cancer to treatment with taxanes.
ƒƒ Histone deacetylase inhibitors are potential new drugs for the treatment of endometrial cancer.
Endometrial cancer as a hereditary tumor
ƒƒ Some cases of endometrial cancer are hereditary tumors. Patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer),
Cowden syndrome and Peutz–Jeghers syndrome, which are hereditary diseases, have a higher risk for endometrial cancer than the
general population. MSH6, a mismatch repair gene, PTEN and LKB1/STK11 have been identified as disease-related genes in these
hereditary conditions.
ƒƒ Lynch syndrome is found in approximately 2% of all types of endometrial cancer.
ƒƒ The lifetime risk of endometrial cancer is 40–60% in females with Lynch syndrome. Therefore, screening for endometrial cancer is
recommended for these patients and their relatives. The Amsterdam II Criteria are used for diagnosis of Lynch syndrome, but some
cases of Lynch syndrome-related endometrial cancer do not meet these criteria. Microsatellite instability and genetic analyses of
mismatch repair genes are useful in these cases.
ƒƒ Endometrial cancer that specifically occurs in the lower uterine body is referred to as carcinoma of the lower uterine segment and has a
hereditary predisposition. Carcinoma of the lower uterine segment is related to Lynch syndrome; therefore, it is a characteristic
phenotype of endometrial cancer that occurs in patients with Lynch syndrome.
ƒƒ Elucidation of disease-related genes in hereditary endometrial cancer and understanding of the carcinogenic mechanism will contribute
to early detection and prevention of endometrial cancer.

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www.icgc.org
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