Hereditary Non-polyposis Colorectal Cancer/Lynch Syndrome
in Korean Patients with Endometrial Cancer
Myong Cheol Lim1, Sang-Soo Seo1, Sokbom Kang1, Moon-Woo Seong2, Bo-Yon Lee3and Sang-Yoon Park1,*
1Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center,2Department of Laboratory
Medicine, Center for Clinical Services, Research Institute and Hospital, National Cancer Center, Goyang-si,
Gyeonggi-do and3Department of Obstetrics and Gynecology, Kyunghee University Medical Center, Kyung-Hee
University, Dongdaemoon-gu, Seoul, South Korea
*For reprints and all correspondence: Sang-Yoon Park, Center for Uterine Cancer, Research Institute and Hospital,
National Cancer Center, 323, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, South Korea. E-mail: sypark.ncc@
Received November 12, 2009; accepted June 30, 2010
Objective: We investigate the frequency of hereditary non-polyposis colorectal cancer among
Korean endometrial cancer patients according to two clinical criteria and the uptake rate of a
genetic test and genetic status of such patients in routine clinical practice.
Methods: This was a retrospective study involving 161 consecutive endometrial cancer
patients. Patients were classified into clinical and suspected hereditary non-polyposis colorec-
tal cancer. Using direct sequencing, germline mutations were analyzed in the MLH1 and
Results: There were four (2.5%) clinical hereditary non-polyposis colorectal cancer patients,
three of whom underwent genetic testing, and a mutation (c.882delT) in the MSH2 gene was
identified in one patient. There were also 14 (8.7%) suspected hereditary non-polyposis color-
ectal cancer patients, 6 of whom underwent genetic testing; 1 [1/6 (16.7%)] patient had a
mutation (c.1757_1758insC) in the MLH1 gene and 1 patient had a sequence variant of
unknown significance (c.1886A , G) in the MSH2 gene. Half of the patients (9 of 18) who
met clinical or suspected hereditary non-polyposis colorectal cancer criteria declined genetic
testing mainly for the reason of financial factor (8 of 9).
Conclusions: The proportion of hereditary non-polyposis colorectal cancer [11.2% (18 of
161)] was significant to offer genetic counseling and genetic testing in Korean endometrial
cancer patients. Optimal financial support is crucial to increase the uptake rate of a genetic
Key words: MLH1 – MSH2 – Koreans – hereditary disease – endometrial cancer
The incidence of endometrial cancer has been increasing
over the past decade in Korea (1). Inherited factors are
suggested as one of the most important risk factors for endo-
metrial cancer (2). In addition to rare Mendelian-inherited
syndromes with a predisposition to endometrial cancer, such
as Muir Torre, Cowden and Turcot syndromes, hereditary
non-polyposis colorectal cancer (HNPCC) is a common
autosomal dominant condition characterized by the develop-
ment of colon and endometrial cancers. The genes that are
responsible for repair of mismatched DNA are defective in
families with this syndrome (2). HNPCC is caused by several
germline mutations in the DNA mismatch repair (MMR)
genes, MLH1, MSH2, PMS1, PMS2 and MSH6 (3–6).
The Amsterdam criteria, the first clinical criteria for the
diagnosis of HNPCC (c-HNPCC), were established in 1991
# The Author (2010). Published by Oxford University Press. All rights reserved.
Jpn J Clin Oncol 2010;40(12)1121–1127
Advance Access Publication 21 October 2010
by guest on October 19, 2015
based on colorectal cancers (7). In 1999, the Amsterdam cri-
teria were revised (8). The new criteria, the Amsterdam cri-
teria II, include colorectal cancers and cancers of the
endometrium, small bowel, renal pelvis and ureters (8). The
Amsterdam criteria II are so strict that many patients with
MMR gene mutations are not included according to these
criteria (9). The suspected HNPCC (s-HNPCC) criteria
include families that do not fulfill the Amsterdam criteria,
but in whom HNPCC is nevertheless strongly suspected (9).
Women with mutations in DNA MMR genes have a risk for
endometrial cancer by age 70 of ?42–60% in Western
populations (10,11). In the Korean population, very few
reports on this issue in endometrial cancer patients exist
Therefore, we undertook this study with two objectives.
The first was to elucidate the frequency of HNPCC in
Korean endometrial cancer patients and determine the
genetic status in such patients from our routine clinical prac-
tice. The second was to investigate the uptake rate of genetic
testing for HNPCC and the cause of non-uptake of a genetic
test in such patients.
PATIENTS AND METHODS
This retrospective study was approved by an institutional
review board. Between January 2005 and June 2008, 161
endometrial cancer patients who were treated at the National
Cancer Center, Korea, and the members of their families
were interviewed for information on family history of any
cancers, with specific reference to any history of
HNPCC-associated cancers, such as cancer of the colon,
endometrium, small intestine and urinary tract (Tables 1 and
2). All patients were confirmed pathologically to have endo-
metrial cancer. Patients who understood that they would
receive the results and counseling regarding the implications
underwent genetic testing. They were informed of the possi-
bility that the genetic testing and the results could lead to
Written informed consent was obtained from each patient
who agreed to the genetic testing. Ethylenediaminetetraacetic
acid-anticoagulated blood samples were obtained by phlebot-
omy from each patient. The entire coding region and the
exon–intron boundaries of the MLH1 and MSH2 genes in
patients with endometrial cancer have been scanned at Green
Cross Reference Laboratory, Yongin-si, Korea.
Genetic DNA was isolated from white blood cells of periph-
eral blood using a Puregene DNA Purification kit (Gentra
System, Minneapolis, MN, USA), following the manufac-
turer’s instructions. DNA concentrations were determined
using a DU 800 spectrophotometer (Beckman Coulter,
Fullerton, CA, USA). Whole exon and exon–intron bound-
aries were included in direct sequencing. The PCR mixture
(10 ml) contained 1.0 ml of 10? PCR buffer (Takara, Tokyo,
Japan), 0.7 ml each of 2.5 mM dNTP (Takara), 0.3 mM each
primer (Bioneer Corp., Chungwon, Korea), 0.5 U of
Taq-DNA polymerase (Takara) and 1 ml (0.5 mg) of
genomic DNA. The thermal cycler (Biometra T Gradient
PCR, Gottingen, Germany) protocol was as follows: 35
cycles of 30 s denaturation at 958C, 30 s annealing at 608C
(up to 658C) and 30 s extension at 728C. There was a 5 min
pre-incubation at 958C before commencing a cycle and a
10 min additional extension at 728C after completion of the
cycles. Amplified DNA (1.5 ml) was incubated with 2 U of
shrimp alkaline phosphatase and 5 U of exonuclease I (USB
Corp., Cleveland, OH, USA) at 378C for 15 min. The
enzymes were inactivated by incubation at 808C for 15 min,
after which the DNA was denatured at 958C for 15 min. The
presence of a PCR product was determined using agarose
gel electrophoresis. Cycle sequencing was performed using a
BigDye Terminator Cycle Sequencing Ready Reaction kit
(v3.0; Applied Biosystems, Foster City, CA, USA) and an
automated ABI Prism 3100 Genetic Analyzer (Applied
Of the 161 patients, there were four (2.5%) c-HNPCC
patients fulfilling the Amsterdam criteria II (Figure 1). Three
of the four c-HNPCC patients underwent genetic testing.
A germline mutation in the MSH2 gene (c.882delT) was
identified in one patient (Table 3).
Table 1. Revised criteria for clinical HNPCC/Lynch syndrome
(Amsterdam criteria II)
At least three relatives with a HNPCC-associated cancer (colorectal,
endometrial, small bowel, ureter or renal pelvis cancers)
One should be a first-degree relative of the other two
At least two successive generations should be affected
At least one should be diagnosed before age 50 years
Familial adenomatous polyposis should be excluded in the colorectal cancer
case(s), if any
Tumors should be verified by pathologic examination
HNPCC, hereditary non-polyposis colorectal cancer. Adopted from Vasen
et al. (8).
Table 2. Revised criteria for suspected HNPCC/Lynch syndrome
At least two HNPCC-associated cancers in first-degree relatives
(colorectum, endometrium, small intestine and urinary tract), and
Multiple colorectal tumors, or
At least one HNPCC-associated cancer diagnosed before age 50 years or
Development of accompanying cancer in family members (stomach, biliary,
ovary and pancreas)
Adopted from Park et al. (9).
1122Lynch syndrome and endometrial cancer in Korea
by guest on October 19, 2015
Fourteen (8.7%) patients met the revised criteria for
s-HNPCC based on family history (Figure 1). Colon cancer
and endometrial cancer were identified in the first-degree
relatives of eight and six patients, respectively. Renal cell
cancer and cholangiocarcinoma existed with colon cancer at
the same time in one first-degree relative. Gastric cancer
(n ¼ 2), renal cell cancer (n ¼ 1), pancreatic cancer (n ¼ 1),
hepatoma (n ¼ 1) and cervical cancer (n ¼ 1) were identified
in the second-degree relatives of the patients. Six of 14
patients (43%) underwent genetic testing. One patient had a
germline mutation (c.1757_1758insC) in the MLH1 gene,
and one patient had a sequence variant of undetermined sig-
nificance (c.1886A . G) in the MSH2 gene (Table 3).
Of 18 patients who met c-HNPCC or s-HNPCC criteria, 9
patients accepted genetic testing. Of nine patients who
decline the genetic testing, eight patients revealed the finan-
cial factor for the main barrier of genetic testing and one
patient did not revealed the reason for the non-uptake of a
genetic test. Predictive factors such as clinical factors of
endometrial cancer including stage and disease status, off-
spring, religion, economic status and education to uptake a
genetic test was not identified.
Three of the 143 patients who were not classified as
c-HNPCC or s-HNPCC wanted to undergo genetic testing
and no sequence variants were identified (Table 4).
The objective of the current study was to investigate the fre-
quency of HNPCC in Korean endometrial cancer patients
according to the two clinical criteria (c-HNPCC and
s-HNPCC) and to determine the genetic status of the MLH1
and MSH2 genes of such patients. We also evaluated the
uptake rate of a genetic test and the reason for the non-
uptake of a genetic test in Korean endometrial cancer
patients from routine clinical practice for the first time as far
as we know. Eighteen of the 161 endometrial cancer patients
(8.7%) met one of the two clinical criteria for HNPCC, and
deleterious mutations in MLH1 and MLH2 genes were ident-
ified in two of nine HNPCC patients (22.2%). Our results for
the frequency of HNPCC in patients with endometrial cancer
are consistent with a previous study (12).
In the current study, the incidence of patients with
c-HNPCC fulfilling Amsterdam criteria II was 2.5% (4 of
161). This is within the range of previous results in Asian
women (0.5% in Japanese and 6.4% in Chinese) (14,15).
The explanation for the different incidence in Asian
countries might be explained as follows. First, the different
Figure 1. Flow diagram for overall study results in patients with endometrial cancer.†Novel mutation.
Table 3. Genetic profile in three patients with HNPCC/Lynch syndrome
35Suspected HNPCC MLH1
40Suspected HNPCC MSH2
1886A , GQ629R
Jpn J Clin Oncol 2010;40(12) 1123
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Table 4. Incidence of MMR genes in endometrial cancer patients
Genetic test Incidence of deleterious
Unselected patients with endometrial cancer
23.4% (18 of 77) MSI high MLH1 and MSH2 0% (0 of 77) and 0%a
(0 of 18)
32.1% (9 of 28) MSI high MLH1 and MSH20% (0 of 28) and 0%a
(0 of 9)
30.8% (12 of 39) MSI highMLH1 and MSH2 2.6% (1 of 39) and 8.3%a
(1 of 12)
Keio University/Japan 25
22.9% (17 of 74) MSI highMLH1, MSH2 and MSH6 1.4% (1 of 74) and 5.8%a
(1 of 17)
13.9% (9 of 65) MSI highMSH2, MLH1, PMS1 and PMS23.1% (2 of 65) and
22.2%a(2 of 9)
21.7% (118 of 543) MSI high or low (98 of 118
MSI high and 20 of 118 MSI low)
MLH1, MSH2, MSH6 and PMS21.8% (10 of 543) and
7.6%a(9bof 118 MSIþ)
Ohio population/USA 23
28.8% (127 of 441) MSI high
27.6% (35 of 127, MLH1 unmethylated/
MSH6 1.6% (7 of 441) and
5.5%a(7 of 127)
University of Washington
and Indiana University/
23.3% [7 of 30, MSH6 mutation/MLH1
unmethylated þ MSI-H after exclusion of
MSH2 mutation (n ¼ 5)]
Unselected cohort of endometrial cancer patientsMSH6 3.8% (4 of 105)Belfast City Hospital/UK 27
Endometrial cancer patients with high risk (familial history, age or tumor location)
Definition of high risk population
Amsterdam criteria II, 2.7% (4 of 113)MLH1, MSH2 and MSH6 2.7% (3 of 113)Seoul National University
Suspected HNPCC criteria, 7.1% (8 of 113)
MSI high with loss of MMR protein expression
after screening of familial history, 8.9% (101 of
Group 1: Patients with .2 first-degree relatives
with HNPCC-related tumors (colorectal cancer,
endometrial cancer, small intestinal cancer,
urethral or renal pelvic cancer, gastric cancer,
ovarian cancer or breast cancer) and an age at
onset of ,50 years for at least one tumor
MLH1, MSH2 and MSH6 15.0% (18 of 120):
Group A, 15.8% (9 of
57); Group B, 8.3% (4 of
48); Group A&B, 33.3%
(5 of 15)
Five multicenters/Japan 31
Group 2: Patients with .2 synchronous or
metachronous HNPCC-related tumors
(colorectal, endometrial, small intestinal, urinary
system or renal pelvis, gastric, breast or ovarian
cancers), regardless of age at onset
Familial site-specific endometrial cancer defined
as occasional families show clustering of
endometrial cancer, without colon or other
cancers [6.4% (33 of 519)]: 33 EC among 23
MLH1, MSH2 and MSH68.7% (2 of 23) Helsinki University/
Unselected cohort of women diagnosed with
endometrial cancer at ,50 years of age
MLH1, MSH2 and MSH69.0% (9 of 100) Three multicenters/USA30
Unselected cohort of women diagnosed with
endometrial cancer at ,50 years of age
(n ¼ 58): with HNPCC-related cancers (n ¼ 22)
Endometrial cancer in the lower uterine segment
[3.5% (35 of 1009)]
MLH1, MSH2 and MSH68.6% (5 of 58) and
22.7% (5 of 22)
MLH1, MSH2, MSH6 and PMS2 29% (10 of 35)M. D. Anderson Cancer
EC, endometrial cancer; MMR, mismatch repair; MSI, microsatellite instability.
aIncidence of MMR gene mutation in patients with MSI high and/or low.
bOne MSH6 mutation in patients with MSI negative and abnormal immunohistochemical staining for MSH6.
1124 Lynch syndrome and endometrial cancer in Korea
by guest on October 19, 2015
incidence might reflect genetic differences among the three
countries. Second, a limited family structure due to a smaller
family significantly affects such an incidence (16). The
family size is typically decreasing in developed countries.
Third, recall bias might be one of the causes. Family history
is usually identified based on the memory of patient and/or
the family member. The family history in colorectal cancer
patients with HNPCC is not reliable to a certain degree
because the false-positive rate reaches 21% (17). In particu-
lar, the sensitivity of uterine cancer based on the self-
reported family history is quite low (30%) compared with a
database-linked family history (18). Further studies are war-
ranted to determine the exact causes for the different inci-
dence in endometrial cancer patients with HNPCC.
The incidence of MMR gene mutations in patients with
sporadic endometrial cancer ranges from 0 to 3.1% after
microsatellite instability (MSI) screening (19–27). Of those
patients with a positive MSI, the incidence of MMR gene
mutations has been reported to be 0–22.2% (19–26). Even
in an unselected cohort of patients with endometrial cancer,
the incidence of mutated MSH6 was reported to be 3.8%
(27). Currently, high risks suggesting hereditary endometrial
cancermay be involved
HNPCC-related cancer, age and tumor location (12,28–32).
In patients with a family history, the incidence of MMR
gene mutations (MLH1, MSH2 and MSH6) ranged from 2.7
to 33.3% based on criteria (12,29,31). Also, the incidence of
MMR gene mutations is high in young endometrial cancer
patients ,50 years of age (8.6–9.0%) (30,32). Endometrial
cancer in the lower uterine segment is suggestive of heredi-
tary cancer; the incidence of MMR gene mutations in such
patients is 29% (28). We can expect a higher incidence of
MMR gene mutations than current outcomes in endometrial
cancer patients because only parts of the MMR genes
(MLH1, MSH2, MSH6, PMS2 and PMS1) were investigated
in previous studies.
In patients with endometrial cancer, MMR gene mutations
are most prevalent in the MSH2 gene (5.2–7.0%) (30,32).
One MSH2 mutation (c.882delT) was identified in our study.
This mutation was first identified in not only Korean but also
in all races. The loss of MSH2 immunohistochemical (IHC)
expression is highly predictive of identifying an MSH2
mutation (30). One mutation (c.1757_1758insC) in the
MLH1 gene was identified in the current study; Shin et al.
(33) reported that the mutation is a founder mutation inher-
ited from a common Korean ancestor. The prevalence of
MLH1 mutations in endometrial cancer patients was not high
in a previous study (1–1.7%) (30,32). The loss of MLH1
IHC expression is less predictive of identifying an MLH1
mutation because a significant number of MSI-positive endo-
metrial cancers have MLH1 promoter hypermethylation (12).
MSH2 c.1886A . G is one of the well-known missense
variants. The variant has been reported as a pathologic
variant in Koreans (33,34). There are web tools to presume
the functional effect of novel missense variants, such
as PolyPhen (http://genetics.bwh.harvard.edu/pph/), SIFT
(http://sift.jcvi.org/) and PMut (http://mmb2.pcb.ub.es:8080/
PMut/). According to these web analyses, PolyPhen is
thought to be potentially damaging, whereas SIFT and PMut
are thought to be benign. Therefore, there was no clear evi-
dence that the mutation was a pathologic variant, and also
there was no evidence that the mutation was a neutral
mutation. Thus, we can classify the MSH2 c.1886A . G as
a variant of unknown significance.
Mutation analysis in the MSH6 and PMS2 genes was not
performed in the current study. The prevalence of MSH6
mutations in endometrial cancer patients was 1–3.8% in pre-
vious studies (27,30,32). Hirai et al. (31) reported the impor-
tance of genetic studies of MSH6 in the evaluation of
Japanese patients with endometrial cancer and HNPCC (31).
One-half (9 of 18) of such patients had MSH6 mutations of
the evaluated MLH1, MSH2 and MSH6. It has been recently
reported that pathogenic PMS2 mutation is more frequently
identified (4%) than originally expected (35). Therefore, in
the future study on HNPCC, MSH6 and PMS2 should be
considered to be included.
The decision to undergo genetic testing is influenced by a
complex mix of familial, cultural and social life experiences
(36). It has been published that the actual acceptance rate of
genetic testing is lower than the rate of interest in genetic
testing among populations at risk for hereditary cancer
(36,37). Although the predictors of the actual uptake of
genetic testing are indefinite, women who have the
additional risk of endometrial cancer are more interested in
testing for HNPCC than men and subjects with children
compared with subjects without children, who are more
likely to seek genetic testing (36). Lerman et al. (38)
reported that 43% (90 of 208) of HNPCC family members
accept genetic testing and barriers to test acceptance seem to
be a less formal education and the presence of symptoms of
depression. Although most of the patients who met the cri-
teria of HNPCC are actually want to know the endometrial
cancer is hereditary or not, only half of the patients with
endometrial cancer underwent genetic testing in this study.
Main barrier to undergo genetic testing is cost. We believe
insurance coverage for genetic counseling, genetic testing
and genetic prescreening will offer better medical environ-
ment for endometrial cancer patients and their progenies.
Clinical predictors of genetic testing may differ according to
gender, offspring, type of disease, disease status, study popu-
lation, country and study methods. Therefore, further studies
in larger patients groups are needed to clarify this issue.
There were several limitations mainly originated from
study design, retrospective review of routine clinical practice.
First, selection bias and other confounders found in a retro-
spective study were also possibilities in this study. We made
an effort to minimize the selection bias and confounders as
much as possible. Second, IHC staining and MSI were not
analyzed in this study, because these tests were performed
inconsistently in 33.5% (54 of 161) of the study population
and 52.6% (10 of 19) of c-HNPCC or s-HNPCC patients.
If the stringent clinical criteria (c-HNPCC) was satisfied,
Jpn J Clin Oncol 2010;40(12) 1125
by guest on October 19, 2015
a direct genetic test is the proper step without the result of a
screening test such IHC staining and MSI analysis (39). The
direct genetic test without a screening test could be rec-
ommended even in s-HNPCC patients from small family
(12). Although IHC staining offers cost-effective strategy to
find patients with mismatch gene mutation (39), trivial limit-
ations exist to select a specific gene because of concurrent
loss of MSH2 with MSH6: these act together due to abroga-
tion of the Mutsa complex formed by MSH2 and MSH6
proteins (40). And MLH1 protein expression from
MLH1-promoter hypermethylation without germline MLH1
mutation in 15% of the patients with endometrial cancer
cause an unnecessary genetic test (41). Accuracy of MSI-H
as a surrogate marker for HNPCC is not perfect and reaches
?90% (42,43). Although we did not evaluate the non-uptake
of IHC staining and MSI analysis specifically, significant
portion of the patients chose a direct genetic test to avoid
revisit of hospital after the positive result of a screening test
for convenience and shortening the waiting time for the final
outcome. Generally, the mutational genetic test is quite
expensive (.$2000 USD just for MSH2 and MLH1) and
three-step process (IHC staining ! MSI analysis ! genetic
test) is accepted as a cost-effective approach in USA (39,44).
Although cost-effectiveness was not investigated in Korea,
patients favor a direct genetic test: one of the causes is rela-
tively cheap cost of the genetic test (,$600 USD for MSH2
and MLH1) in Korea. Third, genetic testing of the MMR
gene was limited to the MLH1 and MSH2 genes. Clinical
usefulness of MSH6 was belatedly identified in 1999 com-
pared with MLH1 and MSH2 genes which were identified in
1994 and 1993, respectively (45–47). It is in this context
that MSH6 was recently available in clinical practice field,
and currently, we have included MSH6 for one of the genetic
tests in patients with HNPCC. Fourth, the separation of
family due to the Korean War was sometimes an obstruction
of the completeness of pedigree analysis (48). Some patients
did not know their parents’ causes of death. Therefore, the
real proportion of HNPCC in Korean endometrial cancer
patients may be more than that revealed in the current study.
In conclusion, this study provides the first clinical
practice-based result for the frequency of HNPCC and the
acceptance rate of genetic testing in Korean endometrial
cancer patients. We found that 11.2% of Korean endometrial
cancer patients met the criteria for c-HNPCC or s-HNPCC.
Half of the c- and s-HNPCC patients accept genetic testing;
main reason of the non-uptake of a genetic test is cost. Two
deleterious germline mutations in the MLH1 and MSH2
genes were identified among three clinical HNPCC and six
s-HNPCC patients (22%). Until more definitive, larger pro-
spective studies are made available; our study results may
assist gynecologic oncologists and gynecologists in their
approach at the time of genetic counseling and genetic
testing in Korean patients with endometrial cancer. Financial
support from government healthcare system and private
health insurance is essential for optimal approach to genetic
screening (IHC staining and MSI analysis) and genetic
This study was supported by National Cancer Center,
Republic of Korea.
The authors would like to thank Ju Hee Park at Seoul
National University College of Medicine, Seoul, Korea, for
her efforts in gathering the data in part.
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