DNA Mismatch Repair (MMR) Genes and Endometrial Cancer

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DNA Mismatch Repair (MMR)
Genes and Endometrial Cancer
Kenta Masuda and Kouji Banno et al.*
Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo
Japan
1. Introduction
The incidence of endometrial cancer among malignant gynecological tumors has increased
with lifestyle and environmental changes. In the US, 40,000 patients are diagnosed with
endometrial cancer annually, and 7,500 patients die of this disease (Jemal et al., 2009).
The number and prevalence of cases of endometrial cancer have increased worldwide
and control of this cancer is urgently required. However, many aspects of the mechanism
of carcinogenesis and pattern of advancement are unclear. Environmental factors such
as obesity and a high estrogen level are thought to play important carcinogenic roles, but
a close association with hereditary disposition has also been suggested, since double
cancer and an increased incidence of cancer in relatives are common in patients with
endometrial cancer.
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a
hereditary disease in which there is frequent development of colorectal, endometrial, and
ovarian cancers. The cause is thought to be mutation of the DNA mismatch repair (MMR)
gene in germ cells. However, the conventional explanation of the mechanism involving
genetic changes - mutations of cancer-related genes - is inadequate and epigenetic changes
in endometrial cancer are now being examined. In particular, aberrant DNA methylation is
thought to play a key role in endometrial carcinogenesis. Breakdown of the DNA mismatch
repair mechanism due to DNA hypermethylation plays a particularly important role in the
development of endometrial cancer.
2. Lynch syndrome
Lynch syndrome is a hereditary disease that includes frequent development of colorectal,
endometrial, and ovarian cancers, and which is inherited in an autosomal dominant
manner. Lynch syndrome is caused by a hereditary defect in the DNA mismatch repair
(MMR) gene and the incidences in colorectal and endometrial cancers are 2-3% and 1-2%,
respectively (Hampel et al., 2006). This syndrome was initially reported by Wartin et al. in
1913 in a family with a high risk of development of colorectal cancer. Subsequent analysis of
* Kouji Banno, Megumi Yanokura, Iori Kisu, Arisa Ueki, Asuka Ono, Yusuke Kobayashi, Hiroyuki
Nomura, Akira Hirasawa, Nobuyuki Susumu and Daisuke Aoki
Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan

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this family led Lynch to propose the disease concept of cancer family syndrome in 1971
(Lynch HT et al., 1971, 2000).
Six MMR genes, the causative genes in Lynch syndrome, have been cloned: hMSH2, hMLH1,
hMSH3, hMSH6, hPMS1 and hPMS2. An aberration in one of these genes prevents accurate
repair of base mismatches produced during DNA replication and repair. In Lynch
syndrome with a hMLH1 or hMSH2 mutation, the frequencies of colorectal and endometrial
cancers are 68% and 62%, respectively, and the lifetime risk of developing endometrial
cancer is higher than that for colorectal cancer in women (Resnick et al., 2009).
Diagnosis of Lynch syndrome is based on clinical criteria. In 1990, the International
Collaborative Group (ICG)-HNPCC established the following diagnostic criteria for
HNPCC, which are referred to as the classical Amsterdam Criteria: 1) HNPCC is diagnosed
when 3 or more patients with histologically confirmed colorectal cancer are present in a
family line and one is a first relative of the other two; 2) colorectal cancer develops over two
generations; and 3) one case is diagnosed at younger than 50 years old (Vasen et al., 1991). In
1999, the new Amsterdam Criteria (Amsterdam II) (Vansen et al., 1999) (Table 1) were
published.
Table 1. Clinical Diagnostic Criteria for HNPCC (FAP, familial adenomatous polyposis)
These criteria address endometrial cancer, small intestinal cancer, urethral cancer, and
kidney cancer, in addition to the colorectal cancer included in the classic criteria.
3. DNA mismatch repair (MMR) gene and endometrial cancer
DNA mismatch repair (MMR) system corrects DNA base pairing errors in newly replicated
DNA. Mispaired nucleotides may be present after DNA replication, along with small
insertion/deletion mutations that tend to occur at repetitive sequences. The MMR system is
an excision/resynthesis system that can be divided into 4 phases: (i) recognition of a
mismatch, (ii) recruitment of repair enzymes, (iii) excision of the incorrect sequence, and (iv)
resynthesis by DNA polymerase using the parental strand as a template. This system is
conserved through evolution from bacteria to human (Jascur & Boland., 2006).
An aberration in one of MMR genes prevents accurate repair of base mismatches produced
during DNA replication, resulting in production of a DNA chain of altered length,
particularly in highly repeated sequences (microsatellites). This phenomenon is called

DNA Mismatch Repair (MMR) Genes and Endometrial Cancer 487
microsatellite instability (MSI) and can lead to an increased frequency of errors in target
genes involved in carcinogenesis, resulting in cancerization of the cell. Among the MMR
genes, germline mutations of hMLH1 on chromosome 3 and hMSH2 on chromosome 2 are
thought to cause most cases of HNPCC. Mutation of hMSH6 has also been proposed to be
important for development of HNPCC-associated endometrial cancer, but the details are
unclear (Fig. 1) (Banno et al., 2009).
Fig. 1. The DNA mismatch repair mechanism in humans
4. Differences in the risk for endometrial cancer between carriers of various
MMR gene mutations
Differences in phenotypes and cancer risks between DNA mismatch repair gene mutations
in patients with Lynch syndrome have been widely investigated. Early studies comparing
colorectal cancer (CRC) with other cancers indicated that patients with a hMSH2 mutation
had a higher risk for cancer other than CRC compared to patients with a hMLH1 mutation
(Vasen et al., 1996). Further studies in Germany, Finland and France showed that families
with a hMSH2 mutation had a higher risk for endometrial cancer compared to those with a
hMLH1 mutation (Parc, 2003; Peltomaki, 2001; Vasen, 2001). However, most recent studies
have found no difference in the risk for endometrial cancer between genotypes. Thus,
Goecke et al. compared 435 and 553 patients in Germany with confirmed or probable
hMLH1 and hMSH2 mutations, respectively, and found significant differences in the risk for
colorectal, gastric and prostate cancers, but not in the risk for endometrial cancer (Goecke et
al., 2006). Kastrinos et al. conducted a large cross-sectional study in 112 unrelated patients
with a hMLH1 mutation and 173 with a hMSH2 mutation in the United States and showed
that the hMLH1 carriers had a higher prevalence of colorectal cancer than the hMSH2

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carriers, whereas the prevalence of endometrial cancer was similar in the two groups.
Extracolonic Lynch syndrome-associated tumors, other than endometrial cancer,
predominate in hMSH2 carriers, with a higher tumor burden among family members
(Kastrinos et al., 2008).
Therefore, it is very important to clarify the MMR mutations associated with a high cancer
risk for management of patients and family members. Based on the results of studies to date,
there is no significant difference in the risk of endometrial cancer for patients with different
MMR mutations.
5. Clinical diagnostic criteria for Lynch syndrome
Since the Amsterdam Criteria for Lynch syndrome were proposed in 1991, several other
diagnostic criteria, including the Japanese Criteria and the Bethesda Criteria, have been
published. The confusion caused by the different criteria was resolved by revision of the
Amsterdam Criteria by the ICG-HNPCC in 1998, to give the new Amsterdam Criteria
(Vasen et al., 1999) (Table 1). These criteria address endometrial cancer, small intestinal
cancer, urethral cancer, kidney cancer, and colorectal cancer. Cases not meeting the classical
Amsterdam Criteria may meet the new Amsterdam Criteria, and this has resulted in an
increased number of cases diagnosed as Lynch syndrome. In addition, discovery of Lynch
syndrome is now possible through investigation of familial histories of endometrial cancer
patients. The revision also recognized the importance of cooperation among gynecologists
for identification of Lynch syndrome. However, one concern with the new criteria is the
omission of ovarian, breast and stomach cancer, which may also be associated with Lynch
syndrome.
The 1999 revised Amsterdam criteria II include endometrial cancer as a Lynch syndrome-
related tumor, but women who develop endometrial cancer as the initial cancer and patients
with a family tree with insufficient details are not included; thus, a high false negative rate
has been reported based on these criteria (Resnick et al., 2009). For colorectal cancer, the
Bethesda criteria require MSI testing, but this is not applicable for patients who develop
endometrial cancer as the initial cancer. Thus, there is a need to establish criteria for
selection of patients with endometrial cancer who should undergo screening (Garg &
Soslow, 2009).
6. Carcinoma of the lower uterine segment (LUS) and Lynch syndrome
Endometrial cancer arises from the uterine body and fundus in many cases, but can also
originate from the lower region of the uterine body through the upper region of the cervix.
Such tumors are referred to as carcinoma of the lower uterine segment (LUS) or isthmus,
and account for 3-6.3% of all cases of endometrial cancer. The association of carcinoma of the
LUS with Lynch syndrome has attracted recent attention. The frequency of Lynch syndrome
in general endometrial cancer is 1-2% (Hampel et al., 2006). In contrast, Lynch syndrome has
a high frequency in cases of carcinoma of the LUS, with one report in the US suggesting that
29% of such cases could also be diagnosed with Lynch syndrome and that the hMSH2
mutation was present at a high frequency in these cases (Westin et al., 2008). Demonstration
of an association between carcinoma of the LUS and Lynch syndrome in a large-scale survey
would allow patients with carcinoma of the LUS to be classified as a high-risk group for
Lynch syndrome (Masuda et al., 2011).

DNA Mismatch Repair (MMR) Genes and Endometrial Cancer 489
7. Screening for endometrial cancer and prophylactic hysterectomy in Lynch
syndrome
Women with Lynch syndrome have a high risk for endometrial cancer, with a life-long
incidence of 40% to 60%, which is similar to or greater than that of colon cancer (Aarno et al.,
1999). Therefore, a woman diagnosed with Lynch syndrome should undergo screening or
prophylactic hysterectomy.
Potential screening methods include transvaginal ultrasound and endometrial biopsy.
Transvaginal or transabdominal sonography is used to evaluate endometrial conditions and
thickness. Some studies have shown a high false-positive rate and poor efficacy (Rijcken,
2003; Dove-Edwin, 2002), while others have shown high sensitivity and negative predictive
values (Lécuru et al, 2010); therefore, the effect of this approach is unclear. Endometrial
biopsy is not used for general screening, but may be useful for patients with Lynch
syndrome with a high risk for endometrial cancer. Thus, women who have a DNA
mismatch repair gene mutation or a family history of this mutation should undergo a biopsy
every year at the age of 30-35 (Lindor et al, 2006).
Prophylactic hysterectomy has not been thought to reduce the cancer risk in women with
Lynch syndrome. In 1997, the Cancer Genetics Studies Consortium suggested that there was
insufficient evidence to recommend that women with Lynch syndrome should have
prophylactic surgery to reduce the risk of gynecologic cancer (Burke et al, 1997). However,
prophylactic hysterectomy has been realistically conducted in some institutions. The effects
of prophylactic hysterectomy are of interest. Schmeler et al. (Schmeler et al., 2006) showed
that prophylactic hysterectomy had a cancer-protective effect based on a retrospective
cohort analysis in 315 women with a detected hMLH1, hMSH2 or hMSH6 germline mutation
from 1973 to 2004. Outcomes were compared between 61 patients who underwent
hysterectomy for prophylaxis or benign disease and 210 patients who did not undergo
prophylactic hysterectomy. None of the 61 patients in the hysterectomy group developed
endometrial cancer, whereas 69 (33%) in the non-hysterectomy group had endometrial
cancer. These results indicate that prophylactic hysterectomy significantly decreased the
development of endometrial cancer.
These results suggest that further studies should be conducted to compare the morbidity
and mortality between screening using sonography or endometrial biopsy and prophylactic
surgery.
8. Microsatellite instability (MSI) and endometrial cancer
Microsatellite instability occurs when the mismatch repair system is damaged.
Microsatellites are DNA sequences of repeating units of 1 to 5 base pairs. Abnormalities in
the mismatch repair system may cause replication errors in the repeating unit, leading to
changes in length that are referred to as MSI. MSI caused by MMR gene aberration is
detectable by PCR using microsatellite markers. In screening for Lynch syndrome, use of 5
microsatellite markers, two mononucleotide repeats (BAT26 and BAT25) and three
dinucleotide repeats (D5S346, D2S123, and D17S250), is recommended (Boland et al., 1998).
MSI is observed in certain types of cancer, including 20 to 30% of cases of endometrial
cancer (Kanaya et al., 2003). These results suggest that MMR gene abnormalities occur
frequently in endometrial cancer.

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To investigate the status and characteristics of familial endometrial cancer, Banno et al.
(Banno et al., 2004a) surveyed the familial and medical histories of 385 patients who
underwent treatment for endometrial cancer. MSI analysis was performed in 38 of these
patients. The familial histories showed that 2 of the 385 cases met the new Amsterdam
Criteria for Lynch syndrome, giving a rate of Lynch syndrome of about 0.5%. Investigation
of familial accumulation of cancer in 890 relatives (439 men and 451 women) of the 38
endometrial cancer patients who underwent MSI analysis revealed high incidences of
endometrial cancer, colorectal cancer and ovarian cancer, suggesting that a hereditary factor
common to Lynch syndrome is also involved in endometrial cancer. MSI analysis detected
at least one of 5 microsatellite markers (D2S123, D3S1284, D5S404, D9S162: microsatellite
loci containing CA repeats and hMSH2 intron 12: a polyA-sequence-containing
microsatellite locus) in 12 of the 38 cases (31.6%). This rate is very high compared to MSI in
cancers of other organs, demonstrating that abnormal DNA mismatch repair plays an
important role in endometrial cancer. The patients with MSI showed a tendency to have
double cancer (such as ovarian cancer) compared with patients with microsatellite stability
(MSS), although the difference was not significant (27% vs. 15%). Regarding prognosis, none
of the MSI-positive cases were fatal (0/11, 0%), while 5 MSI-negative (MSS) cases were fatal
(5/27, 19%). The difference was not significant, but this tendency is similar to that for Lynch
syndrome-associated colorectal cancer. The incidences of moderately differentiated
adenocarcinoma G2 (36%) and poorly differentiated adenocarcinoma G3 (18%) tended to be
higher in MSI-positive endometrial cancer, although again the difference was not
significant. These findings appear contradictory with the favorable prognosis, but
interestingly they may reflect the biological characteristics of endometrial cancer induced by
abnormal DNA mismatch repair (Banno et al., 2004b).
9. DNA hypermethylation and endometrial cancer
Epigenetics refers to the information stored after somatic cell division that is not contained
within the DNA base sequence. Recent findings have shown that epigenetic changes -
selective abnormalities in gene function that are not due to DNA base sequence
abnormalities - play a significant role in carcinogenesis in various organs. In particular, the
relationship between cancer and aberrant hypermethylation of specific genome regions has
attracted attention. A completely new model for the mechanism of carcinogenesis has been
proposed in which hypermethylation of unmethylated CpG islands in the promoter regions
of cancer-related genes in normal cells silences these genes and leads to the cell becoming
cancerous (Figure 2).
The main difference between epigenetic abnormalities and genetic abnormalities such as
gene mutations is that epigenetic changes are reversible and do not involve changes in base
sequence. This suggests that restoration of gene expression is possible and that epigenetic
mechanisms may constitute important molecular targets for treatment. Attempts have
begun to detect aberrant DNA methylation in cancer cells present in minute quantities in
biological samples and to apply the results to cancer diagnosis, prediction of the risk of
carcinogenesis, and definition of the properties of a particular cancer. The MMR gene
hMLH1 is a typical gene that is silenced by DNA methylation. In endometrial cancer, hMLH1
silencing is found in approximately 40% of cases and is an important step in the early stages
of carcinogenesis, with the loss of DNA mismatch repair function proposed to lead to
mutation of genes such as PTEN. In patients with endometrial cancer, Banno et al. found

DNA Mismatch Repair (MMR) Genes and Endometrial Cancer 491
aberrant hypermethylation of hMLH1, APC, E-cadherin, and CHFR in 40.4%, 22.0%, 14.0%,
and 13.3% of cases, respectively. A significant decrease in protein expression was found in
patients with aberrant methylation of hMLH1 (P<0.01) and E-cadherin (P<0.05), and
aberrant methylation of hMLH1 was also found in 14.3% of patients with atypical
endometrial hyperplasia (AEH).
Fig. 2. Inactivation mechanism of cancer genes
However, no aberrant methylation of the four cancer-related genes was found in patients
with a normal endometrium. These results indicate that aberrant methylation of specific
genes associated with carcinogenesis in endometrial cancer does not occur in a normal
endometrium. Aberrant methylation of hMLH1 was most frequent, and the observation of
this phenomenon in AEH, which is found in the first stage of endometrial cancer, supports
the hypothesis that aberrant methylation of hMLH1 is an important event in carcinogenesis
in endometrial cancer (Banno, 2006; Muraki, 2009).
10. Conclusion
The DNA mismatch repair pathway is important in carcinogenesis of endometrial cancer.
Recent analyses have shown that the MMR pathway can be impaired via both genetic
and epigenetic mechanisms. Genetically, Lynch syndrome in cases of endometrial cancer
is caused by hereditary defects in the MMR genes. However, there have been fewer
studies on endometrial cancer compared to colorectal cancer in patients with Lynch
syndrome. Clarification of the pathology and development of screening and genetic tests
are required for further progress in this area. Epigenetic research in endometrial cancer
suggests that damage to the mismatch repair system plays a significant role in

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carcinogenesis and that DNA hypermethylation is important in this mechanism. Many
attempts are currently being made to use epigenetic abnormalities as new methods of
diagnosis and treatment based on control of methylation. Further studies of the genetic
and epigenetic mechanisms may have potential for diagnosis, risk assessment, and
treatment of endometrial cancer.
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