The study of mismatch repair in endometrial cancer patients with a family history of cancer
Aim: To assess the expression of mismatch repair (MMR) proteins MSH2 and MLH1 and carry out microsatellite analysis in patients with endometrial cancer (EC) with regard to the family history of cancer. Materials and Methods: Morphological and immunohistochemical study was performed on tumor tissue s...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1455552019-01-24T01:23:10Z The study of mismatch repair in endometrial cancer patients with a family history of cancer Buchynska, L.G. Brieieva, O.V. Nekrasov, K.A. Nespryadko, S.V. Original contributions Aim: To assess the expression of mismatch repair (MMR) proteins MSH2 and MLH1 and carry out microsatellite analysis in patients with endometrial cancer (EC) with regard to the family history of cancer. Materials and Methods: Morphological and immunohistochemical study was performed on tumor tissue samples of 49 EC patients. Microsatellite instability was determined using PCR with primers which flank microsatellite region BAT-26. Results: A tendency to a decreased expression of both MSH2 and MLH1 markers in a group of EC patients with a family history of cancer as compared with a group without aggregation of cancer in family history was observed (labeling index — LI — was 36.1 ± 8.1% and LI 20.7 ± 9.1% versus LI 48.0 ± 5.8% and 33.8 ± 5.8%, respectively). It was determined that the number of EC patients with tumors deficient by expression of MMR markers was reliably higher in a group of patients with a family history of cancer than in a group of patients without aggregation of cancer in family history (р < 0.05). It was shown that in a group of EC patients with a family history of cancer, MMR-proficient tumors were detected in 38.5% of cases. Microsatellite instability was determined in 10.7% of EC patients including one patient with aggregation of Lynch-associated tumors in family history. Conclusion: Family history of cancer of EC patients is associated with malfunctioning of the MMR system as well as may be related to alternative molecular mechanisms. Key Words: endometrial cancer, mismatch repair, microsatellite instability, family history of cancer, Lynch syndrome. 2015 Article The study of mismatch repair in endometrial cancer patients with a family history of cancer / L.G. Buchynska, O.V. Brieieva, K.A. Nekrasov, S.V. Nespryadko // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 272-276. — Бібліогр.: 33 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145555 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Buchynska, L.G. Brieieva, O.V. Nekrasov, K.A. Nespryadko, S.V. The study of mismatch repair in endometrial cancer patients with a family history of cancer Experimental Oncology |
| description |
Aim: To assess the expression of mismatch repair (MMR) proteins MSH2 and MLH1 and carry out microsatellite analysis in patients with endometrial cancer (EC) with regard to the family history of cancer. Materials and Methods: Morphological and immunohistochemical study was performed on tumor tissue samples of 49 EC patients. Microsatellite instability was determined using PCR with primers which flank microsatellite region BAT-26. Results: A tendency to a decreased expression of both MSH2 and MLH1 markers in a group of EC patients with a family history of cancer as compared with a group without aggregation of cancer in family history was observed (labeling index — LI — was 36.1 ± 8.1% and LI 20.7 ± 9.1% versus LI 48.0 ± 5.8% and 33.8 ± 5.8%, respectively). It was determined that the number of EC patients with tumors deficient by expression of MMR markers was reliably higher in a group of patients with a family history of cancer than in a group of patients without aggregation of cancer in family history (р < 0.05). It was shown that in a group of EC patients with a family history of cancer, MMR-proficient tumors were detected in 38.5% of cases. Microsatellite instability was determined in 10.7% of EC patients including one patient with aggregation of Lynch-associated tumors in family history. Conclusion: Family history of cancer of EC patients is associated with malfunctioning of the MMR system as well as may be related to alternative molecular mechanisms. Key Words: endometrial cancer, mismatch repair, microsatellite instability, family history of cancer, Lynch syndrome. |
| format |
Article |
| author |
Buchynska, L.G. Brieieva, O.V. Nekrasov, K.A. Nespryadko, S.V. |
| author_facet |
Buchynska, L.G. Brieieva, O.V. Nekrasov, K.A. Nespryadko, S.V. |
| author_sort |
Buchynska, L.G. |
| title |
The study of mismatch repair in endometrial cancer patients with a family history of cancer |
| title_short |
The study of mismatch repair in endometrial cancer patients with a family history of cancer |
| title_full |
The study of mismatch repair in endometrial cancer patients with a family history of cancer |
| title_fullStr |
The study of mismatch repair in endometrial cancer patients with a family history of cancer |
| title_full_unstemmed |
The study of mismatch repair in endometrial cancer patients with a family history of cancer |
| title_sort |
study of mismatch repair in endometrial cancer patients with a family history of cancer |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2015 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/145555 |
| citation_txt |
The study of mismatch repair in endometrial cancer patients with a family history of cancer / L.G. Buchynska, O.V. Brieieva, K.A. Nekrasov, S.V. Nespryadko // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 272-276. — Бібліогр.: 33 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-10T21:56:59Z |
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2025-07-10T21:56:59Z |
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| fulltext |
272 Experimental Oncology 37, 272–276, 2015 (December)
THE STUDY OF MISMATCH REPAIR IN ENDOMETRIAL CANCER
PATIENTS WITH A FAMILY HISTORY OF CANCER
L.G. Buchynska1, O.V. Brieieva1*, K.A. Nekrasov2, S.V. Nespryadko3
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine,
Kyiv 03022, Ukraine
2Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv 03680, Ukraine
3National Cancer Institute, MH of Ukraine, Kyiv 03022, Ukraine
Aim: To assess the expression of mismatch repair (MMR) proteins MSH2 and MLH1 and carry out microsatellite analysis in pa-
tients with endometrial cancer (EC) with regard to the family history of cancer. Materials and Methods: Morphological and im-
munohistochemical study was performed on tumor tissue samples of 49 EC patients. Microsatellite instability was determined
using PCR with primers which flank microsatellite region BAT-26. Results: A tendency to a decreased expression of both MSH2 and
MLH1 markers in a group of EC patients with a family history of cancer as compared with a group without aggregation of cancer
in family history was observed (labeling index — LI — was 36.1 ± 8.1% and LI 20.7 ± 9.1% versus LI 48.0 ± 5.8% and 33.8 ±
5.8%, respectively). It was determined that the number of EC patients with tumors deficient by expression of MMR markers was
reliably higher in a group of patients with a family history of cancer than in a group of patients without aggregation of cancer
in fami ly history (р < 0.05). It was shown that in a group of EC patients with a family history of cancer, MMR-proficient tumors
were detected in 38.5% of cases. Microsatellite instability was determined in 10.7% of EC patients including one patient with ag-
gregation of Lynch-associated tumors in family history. Conclusion: Family history of cancer of EC patients is associated with
malfunctioning of the MMR system as well as may be related to alternative molecular mechanisms.
Key Words: endometrial cancer, mismatch repair, microsatellite instability, family history of cancer, Lynch syndrome.
It is known today that approximately 5–10% of ma-
lignant neoplasms occur in the result of hereditary
predisposition to cancer caused by the germinal muta-
tions in genes which are associated with increased risk
of cancer [1, 2]. Endometrial cancer (EC) may occur
due to the series of hereditary cancer syndromes,
among which Lynch syndrome (hereditary non-polypo-
sis colorectal cancer) is the most prevalent. The specific
feature of Lynch syndrome is a presence of germinal
mutations in genes MSH2, MLH1, MSH6, and PMS2,
which belong to the mismatch repair (MMR) system [3].
MMR provides improvement of non-complemen-
tary base pairs, which in high amount emerge in the
process of DNA replication. Genetic or epige netic
disorders of this system cause the development
of microsatellite instability (MSI) that manifests itself
by microdeletions and microinsertions in the regions
of location of mono-, di-, tri- and tetranucleotide re-
peats of DNA. At accumulation of non-repaired micro-
deletions and microinsertions in microsatellites, which
are located in coding and regulatory regions of proto-
oncogenes and suppressor genes, shift of the reading
frame and change of expression of these genes occurs
that can be the reason of malignant transformation [4].
According to some data, effectiveness of functioning
of MMR significantly determines the aggressiveness
of tumor process that can be used at the choice
of EC treatment strategy [5].
In 1913, Lynch syndrome was first time described
by Warthin on the example of family, in the history
of which aggregation of endometrial tumors and gas-
trointestinal cancer was observed. Today Lynch-associ-
ated neoplasms include tumors of colon, endometrium,
gastric, ovary, pancreas, bile ducts, and urogenital
system as well as tumors of some other localization [3].
Lynch syndrome in patients with colorectal cancer
is diagnosed basing on the Amsterdam criteria [6, 7]
and Bethesda recommendations [8, 9]. The last ones,
along with the assessment of family history of proband,
require carrying out of molecular-genetic tests. Re-
cently specified recommendations concerning detec-
tion of individuals with Lynch syndrome among patients
with EC were published [3, 10]. It should be noted that
number of researchers have evaluated the dissemina-
tion of Lynch syndrome via determination of hereditary
mutations and it was detected that its frequency was
within the limits of 2.0–4.6% [11–15].
Some authors assume the existence of particular
hereditary syndrome of EC, at which proband has
a family history of this disease and no mutations in MMR
genes [16]. The last argues the necessity of carrying out
of further studies concerning the detection of peculiari-
ties of cancer pathology aggregation in family history
of patients with EC and its molecular mechanisms.
This research aims to assess the expression
of MMR proteins and analyze MSI in EC patients re-
garding the family history of cancer.
MATERIALS AND METHODS
Morphological, immunohistochemical tests and
microsatellite analysis were carried out on samples
of tumor tissue of 49 patients with EC of I and II stages
Submitted: October 27, 2015.
*Correspondence: E-mail: olha.brie@gmail.com
Abbreviations used: CRC — colorectal cancer; EC — endometrial
cancer; GC — gastric cancer; LI — labeling index; MMR — mis-
match repair; MSI — microsatellite instability.
Exp Oncol 2015
37, 4, 272–276
Experimental Oncology 37, 272–276, 2015 (December) 273
who underwent surgery in the Research Department
of Cancer Gynecology of the National Cancer Institute
of Ministry of Health of Ukraine. Mean age of patients
was 59.0 ± 1.7 years. All patients have given written
informed consent for participation in the study.
To analyze family history of probands, special ge-
nealogical questionnaire, which contained information
on diseases of relatives, life conditions of the patient
and concomitant diseases, was used. As criteria for
attributing of the EC patients to the group of individu-
als with a family history of cancer was the presence
of malignant tumors of female reproductive system
and/or other Lynch-associated tumors in relatives
of probands of I–II degree of the relationship [3].
Morphological study was carried out on the speci-
mens dyed with hematoxylin and eosin. Assessment
of expression of key markers of the MMR-system
was conducted using immunohistochemical method
with monoclonal antibodies MSH2 (clone 25D12) and
MLH1 (clone G168–15) (“Diagnostic BioSystems”,
USA). To visualize mentioned proteins, detection
PolyVue system (“Diagnostic BioSystems”, USA) was
used. Results of immunohistochemical reaction were
assessed by calculation of the number of stained
cells, which was determined in percentage (labeling
index — LI, %). Expression of markers was assessed
in 800–1000 tumor cells.
Microsatellite analysis was carried out using PCR
with primers that flank microsatellite region BAT-26 [17].
Genomic DNA was isolated from tumor tissues and
peripheral blood lymphocytes via phenol-chloroform
extraction. Nucleotide sequence of primers was the
following: Forward: 5�-TGACTACTTTTGACTTCAGCC-3�
and Reverse: 5�- ACCATTCAACATTTTTAACCC-3�. PCR
was carried out in 20 μL of PCR buffer that contained
2.5 mM MgCl2, 200 mM of each dNTP, 0.3 mM of each
primer, 100 ng of DNA and 2 U Taq-polymerase.
The mixture was warmed up to 95 °C for 5 min and 33 cy-
cles of amplification were carried out with parameters:
denaturation 94 °C — 30 s, annealing 58 °C — 30 s and
elongation 72 °C — 30 s.
Products of PCR were separated by electrophoresis
in 15% polyacrylamide gel at 120 V during 12 h and
were stained with SYBR Green. MSI was confirmed
at emergence of alleles, length of which differed from
the normal ones, which were detected in DNA from
peripheral blood lymphocytes.
Statistical processing of data was carried using
program package Statistica 8.0 (StatSoft, Inc.) with the
help of Mann — Whitney nonparametric criterion and
Fisher criterion. Reliable were considered differences
at р < 0.05.
RESULTS AND DISCUSSION
Verification of morphological diagnosis has deter-
mined that all studied endometrial tumors were endome-
trioid adenocarcinomas of various differentiation grades:
6 — well, 25 — moderately and 18 — poorly differentiated
tumors. Immunohistochemical study has detected that
positive expression of MSH2 protein was found in 75.5%
(37 out of 49 cases), and MLH1 protein — 57.1% (28 out
of 49 cases) of endometrial tumors and mean number
of cells, which express these proteins, was 44.6 ± 4.8%
and 30.1 ± 5.0%, respectively (Fig. 1).
a
b
Fig. 1. Expression of MMR proteins MSH2 and MLH1 in modera-
tely differentiated endometrial adenocarcinoma (a); poorly diffe-
rentiated endometrial adenocarcinoma (b). Immunohistochemical
method, stained with Mayer’s hematoxylin, × 400
Clinical and genealogical analysis of family histories
of EC patients has showed that 13 (26.5%) out of 49 pro-
bands had a family history of cancer. It was determined
that mostly tumors of female reproductive system and
gastrointestinal tract were accumulated in families
(Table 1, Fig. 2) that fits our results obtained in previous
studies [18]. Tumors were observed in 5 (71.4%) mo-
thers and 2 siblings (28.6%) among first degree relatives
of EC patients and in 6 aunts (54.7%), 3 grandmothers
(27.3%), 1 uncle (9.0%) and 1 niece (9.0%) among
second degree relatives.
Table 1. Malignant tumors in relatives of EC patients
Degree of relationship
Localization of tumors and their quantity
in proband families
Endome-
trium Breast
Gastro-
intestinal
tract
Ovary Total
І (mother, father, sister, bro-
ther, children)
1 2 3 1 7
ІІ (aunt, uncle, grandmother,
grandfather, nephew, niece)
5 4 2 0 11
Total 6 6 5 1 18
Comparison of expression of MSH2 marker in pa-
tients with EC from the families with a family history
of cancer has not determined reliable difference in the
274 Experimental Oncology 37, 272–276, 2015 (December)
number of MSH2-positive cases as compared to the
group of patients without aggregation of cancer pa-
thology in family history. However, for MLH1 protein,
significant difference was determined between these
indexes in groups of EC patients with aggregation and
without aggregation of cancer in family (p < 0.05) (Ta-
ble 2). Also, it was determined that in a group of EC pa-
tients with a family history of cancer, a tendency to de-
creased expression of MSH2 marker as compared with
a group without aggregation of cancer in family was
observed (LI 36.1 ± 8.1 and 48.0 ± 5.8%, respectively).
The expression of MLH1 changed in the same way
(LI 20.7 ± 9.1 and 33.8 ± 5.8%, respectively).
I
II
III
EC,
50
CRC,
5046 CRC,
74
GC,
55
Fig. 2. Pedigree of proband with EC. In relatives of I and II degree
of relationship, aggregation of Lynch-associated tumors is ob-
served: EC, gastric cancer (GC) and colorectal cancer (CRC)
Taking into account the fact that a lack of at least
one of the MMR-proteins causes the malfuncti oning
of the whole MMR system, we have determined two
groups of tumors by expression of MSH2 and MLH1:
MMR-deficient (lack of both or one of MMR-proteins)
and MMR-proficient (presence of both MMR-pro-
teins) [19, 20]. It was determined that the number
of EC patients with MMR-deficient tumors was reli-
ably higher in a group of patients with a family history
of cancer (8 out of 13) while in a group of patients
without family history of cancer their number was
27.8% (10 out of 36) (p < 0.05) (Table 3).
Table 3. Comparing number of MMR-deficient and MMR-proficient tumors
in EC patients depending on familial aggregation of cancer
Groups of examined patients
Number
of MMR-defi-
cient tumors,
n (%)
Number
of MMR-profi-
cient tumors,
n (%)
Patients with a family history of cancer 8 (61.5) 5 (38.5)
Patients with no family history of cancer 10 (27.8) 26 (72.2)
p p < 0.05 (F test)
Data stated above show that tumors of EC patients
with a family history of cancer are characterized by the
defects in expression of key proteins of the MMR sys-
tem MSH2 and MLH1 to a greater extent than tumors
of patients, which emerged sporadically. The further
analysis of a group of patients with a family history
of cancer has showed that out of 8 EC patients with
MMR-deficient tumors, aggregation of cancer pa-
thology by the type of Lynch syndrome was observed
in 5 (10.2%) of them that allows to pre-include these
patients in the group of patients with suspected Lynch
syndrome. According to the data of literature, for the
final diagnosis of the Lynch syndrome, molecular-
genetic test with detection of hereditary mutations
in MMR genes in patient and her relatives has to be car-
ried out. Such test is recommended to perform after
previous immunohistochemical detection of the
4 MMR-proteins (MSH2, MLH1, MSH6 and PMS2)
and assessment of promoter methylation status
of MLH1 gene in the case of lack of its expression [3].
In three examined EC patients with a family history
of cancer and MMR-deficient tumors in family histo-
ries, along with tumors of gastrointestinal tract, breast
tumors were observed that according to the ideas
of the number of researchers indicates the possibility
of referring of breast tumors to the Lynch-associated
tumors [21, 22], but this issue remains disputable.
In group of 5 EC patients with MMR-proficient tu-
mors and a family history of cancer (38.5%), 2 patients
had familial aggregation of EC, 2 other patients — breast
cancer, and in 1 case — aggregation of gastrointesti-
nal cancers by the type of Lynch syndrome. Presence
of EC in family histories of patients of this group fits the
data of other researchers on the existence of particular
hereditary syndrome of EC, which is not associated
with malfunctioning of MMR-system [11, 23]. Presence
of breast cancer in family histories of EC patients also
may be not random and allows to assume possibi lity
of existence of hereditary syndrome “breast can-
cer — endometrial cancer” that was reported by Wendt
et al. [24]. At the same time, mutations at Lynch syn-
drome occur not only in MSH2 and MLH1 genes, but
also in MSH6 and PMS2 genes. For this reason, one
cannot exclude that in patients with MMR-proficient EC,
hereditary aggregation is caused by germinal mutations
in genes MSH6 and PMS2, expression of which was not
analyzed in this study.
Taking into account that genetic and epigenetic
changes of MMR genes cause MSI, we have carried
out microsatellite analysis by marker BAT-26 in en-
dometrial adenocarcinomas of 28 patients. MSI was
detected in 3 cases (10.7%) (Fig. 3). This rate turned
out to be lower as compared with frequency of MSI,
which was determined by other researchers that pro-
bably is associated with different prevalence of MSI
in different ethnic groups [28]. For instance, accord-
ing to the literature, MSI is detected in 25–30% of all
endometrial carcinomas [25]. It should be noted that
studies of Ichikawa et al. [26], and Risinger et al. [27]
have showed that 75% of Lynch-associated endo-
metrial adenocarcinomas are characterized by pre-
Table 2. Assessment of expression of MMR markers in tumors of EC patients depending on familial aggregation of cancer
Groups of examined patients
Number of tumors with expression of markers, % LI, %
Mean ± SEMSH2 MLH1
Positive expression,
n (%)
Lack expression,
n (%)
Positive expression,
n (%)
Lack expression,
n (%) MSH2 MLH1
Patients with a family history of cancer 9 (70.2) 4 (30.8) 4 (55.5) 7 (54.5) 36.1 ± 8.1 20.7 ± 9.1
Patients without family history of cancer 29 (82.8) 6 (17.2) 29 (80.5) 7 (19.5) 48.0 ± 5.8 33.8 ± 5.8
p p > 0.05 (F test) p < 0.05 (F test) p > 0.05 (Mann —
Whitney test)
p > 0.05 (Mann —
Whitney test)
Experimental Oncology 37, 272–276, 2015 (December) 275
sence of MSI. Among EC patients, in whom MSI was
determined, Lynch-associated tumors were observed
in family history of one patient. Our data on frequency
of MSI among EC patients with a family history of can-
cer may be confirmation of existence of alternative
molecular mechanisms, which cause the development
of hereditary forms of cancer.
L T L T L Ta b c
Fig. 3. Results of microsatellite analysis using BAT-26 marker.
MSI is confirmed in 3 cases (a, b, c) that is evidenced by the
emergence of alleles of other length in tumor DNA (marked
by arrow) as compared with DNA from peripheral blood lym-
phocytes. L — PCR product from lymphocyte DNA, T — PCR
product from tumor DNA
Thus, the results of our study show that family history
of cancer in EC patients is associated with malfunction
of the system of MMR. At the same time, obtained
data allow to assume the existence of other molecular
mechanisms, which stipulate the development of he-
reditary forms of cancer. It also has to be taken into
account that a family history of cancer may be caused
not only by genetic factors, but also by environmental
exogenous factors, which influence the members of the
same family. For instance, the results of studies of Seger
et al. [29] show that risk of EC was higher in relatives
with EC with high body mass index as compared with
patients, whose indexes were low or average.
It should be noted that prognostic impact of MMR
deficiency on outcome of EC remains unclear. Some stu-
dies didn’t find any association between MMR deficiency
and outcome in EC patients [30, 31]. By contrast, Nout
et al. [32] reported association with decreased survival.
In addition, de Jong et al. [33] showed that patients with
the loss of MMR protein expression had a worse disease
specific survival compared to patients with its expression.
Further studies are needed to clarify impact of MMR
status on outcome of the disease in EC patients with
family history of cancer.
Understanding of mechanisms of development
of familial cancers is a basis for the search of new bio-
markers, by which hereditary predisposition to cancer
may be determined. Such approach contributes to the
effective formation of groups with high risk of cancer
and primary prophylaxis of cancer diseases. Detection
of individuals with suspected Lynch syndrome or other
hereditary syndromes among EC patients will allow phy-
sicians to provide these patients and their relatives with
required recommendations concerning the lifestyle and
use adequate procedures to prevent cancer diseases.
CONCLUSIONS
Family history of cancer in EC patients is accom-
panied with the malfunctioning of the MMR-system
that is associated with decreased expression of MMR-
proteins and increase of number of MMR-deficient tu-
mors among EC patients with family history of cancer.
MSI was determined in 10.7% of EC patients. MMR-
proficient tumors were found in 38.5% of EC patients
with aggregation of cancer in family history that may
indicate existence of alternative molecular mecha-
nisms, which cause the development of hereditary
forms of cancer.
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