Genetic polymorphisms of the renin-angiotensin system in breast cancer patients
Background: breast cancer (BC) is one of the most common cancer pathologies in women. Genetic polymorphism of genes of reninangiotensin system (RAS) is considered to be associated with cancer development, in particular, with BC. Aim - to study the influence of polymorphic variants of genes coding fo...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1452132019-01-20T01:23:22Z Genetic polymorphisms of the renin-angiotensin system in breast cancer patients Fishchuk, L.E. Gorovenko, N.G. Original contributions Background: breast cancer (BC) is one of the most common cancer pathologies in women. Genetic polymorphism of genes of reninangiotensin system (RAS) is considered to be associated with cancer development, in particular, with BC. Aim - to study the influence of polymorphic variants of genes coding for RAS components, on the risk of BC development in Ukrainian women. In the study 131 patients with histologically proven diagnosis of BC of I and II stages were enrolled. The control group was composed from 102 women without cancer. Polymorphic variants of AGT, ACE, AT2R1 genes were studied with the use of PCR and PCR-RFLP methods. It has been revealed that the presence of 1166АС genotype of AT2R1 gene elevates the risk of BC development nearly 2-fold. The results of analysis for common group and subgroups distributed by age are different. For women from 18 to 35 years old the significant differences were not found. For women from 36 to 54 years old an increased risk of BC development is determined by the presence of D allele of АСЕ gene. Decreased risk of BC development was associated with the presence of combined genotypes ACE II/ AGT 174TT and ACE II/AGT 235МТ. In women older than 54 years an increased risk of BC development was found to be related to the presence of genotypes 235ТT of AGT gene and 1166АС of AT2R1 gene. The presence of genotype combinations AGT 235ТТ/AGT 174ТМ and AGT 235ТТ/AT2R1 1166AA in women of this age subgroup also significantly increases the risk of BC development. Key Words: breast cancer, renin-angiotensin system, polymorphism, gene. 2013 Article Genetic polymorphisms of the renin-angiotensin system in breast cancer patients / L.E. Fishchuk, N.G. Gorovenko // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 101-104. — Бібліогр.: 22 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145213 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Fishchuk, L.E. Gorovenko, N.G. Genetic polymorphisms of the renin-angiotensin system in breast cancer patients Experimental Oncology |
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Background: breast cancer (BC) is one of the most common cancer pathologies in women. Genetic polymorphism of genes of reninangiotensin system (RAS) is considered to be associated with cancer development, in particular, with BC. Aim - to study the influence of polymorphic variants of genes coding for RAS components, on the risk of BC development in Ukrainian women. In the study 131 patients with histologically proven diagnosis of BC of I and II stages were enrolled. The control group was composed from 102 women without cancer. Polymorphic variants of AGT, ACE, AT2R1 genes were studied with the use of PCR and PCR-RFLP methods. It has been revealed that the presence of 1166АС genotype of AT2R1 gene elevates the risk of BC development nearly 2-fold. The results of analysis for common group and subgroups distributed by age are different. For women from 18 to 35 years old the significant differences were not found. For women from 36 to 54 years old an increased risk of BC development is determined by the presence of D allele of АСЕ gene. Decreased risk of BC development was associated with the presence of combined genotypes ACE II/ AGT 174TT and ACE II/AGT 235МТ. In women older than 54 years an increased risk of BC development was found to be related to the presence of genotypes 235ТT of AGT gene and 1166АС of AT2R1 gene. The presence of genotype combinations AGT 235ТТ/AGT 174ТМ and AGT 235ТТ/AT2R1 1166AA in women of this age subgroup also significantly increases the risk of BC development. Key Words: breast cancer, renin-angiotensin system, polymorphism, gene. |
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Article |
| author |
Fishchuk, L.E. Gorovenko, N.G. |
| author_facet |
Fishchuk, L.E. Gorovenko, N.G. |
| author_sort |
Fishchuk, L.E. |
| title |
Genetic polymorphisms of the renin-angiotensin system in breast cancer patients |
| title_short |
Genetic polymorphisms of the renin-angiotensin system in breast cancer patients |
| title_full |
Genetic polymorphisms of the renin-angiotensin system in breast cancer patients |
| title_fullStr |
Genetic polymorphisms of the renin-angiotensin system in breast cancer patients |
| title_full_unstemmed |
Genetic polymorphisms of the renin-angiotensin system in breast cancer patients |
| title_sort |
genetic polymorphisms of the renin-angiotensin system in breast cancer patients |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2013 |
| topic_facet |
Original contributions |
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http://dspace.nbuv.gov.ua/handle/123456789/145213 |
| citation_txt |
Genetic polymorphisms of the renin-angiotensin system in breast cancer patients / L.E. Fishchuk, N.G. Gorovenko // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 101-104. — Бібліогр.: 22 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT fishchukle geneticpolymorphismsofthereninangiotensinsysteminbreastcancerpatients AT gorovenkong geneticpolymorphismsofthereninangiotensinsysteminbreastcancerpatients |
| first_indexed |
2025-07-10T21:07:05Z |
| last_indexed |
2025-07-10T21:07:05Z |
| _version_ |
1837295600693936128 |
| fulltext |
Experimental Oncology ��� �������� ���� ���ne���� �������� ���� ���ne� ���ne� ���
GENETIC POLYMORPHISMS OF THE RENIN-ANGIOTENSIN
SYSTEM IN BREAST CANCER PATIENTS
L.E. Fishchuk1,*, N.G. Gorovenko2
1SI «Institute of Genetic and Regenerative Medicine of NAMS», Kyiv 04114, Ukraine
2P.L. Shupik National Medical Academy of Postgraduate Education, Kyiv 04112, Ukraine
Background: Breast cancer (BC) is one of the most common cancer pathologies in women. Genetic polymorphism of genes of renin-
angiotensin system (RAS) is considered to be associated with cancer development, in particular, with BC. Aim: To study the influence
of polymorphic variants of genes coding for RAS components, on the risk of BC development in Ukrainian women. Materials and Meth-
ods: In the study 131 patients with histologically proven diagnosis of BC of I and II stages were enrolled. The control group was composed
from 102 women without cancer. Polymorphic variants of AGT, ACE, AT2R1 genes were studied with the use of PCR and PCR-RFLP
methods. Results: It has been revealed that the presence of 1166АС genotype of AT2R1 gene elevates the risk of BC development nearly
2-fold. The results of analysis for common group and subgroups distributed by age are different. For women from 18 to 35 years old the
significant differences were not found. For women from 36 to 54 years old an increased risk of BC development is determined by the
presence of D allele of АСЕ gene. Decreased risk of BC development was associated with the presence of combined genotypes ACE II/
AGT 174TT and ACE II/AGT 235МТ. In women older than 54 years an increased risk of BC development was found to be related to the
presence of genotypes 235ТT of AGT gene and 1166АС of AT2R1 gene. The presence of genotype combinations AGT 235ТТ/AGT 174ТМ
and AGT 235ТТ/AT2R1 1166AA in women of this age subgroup also significantly increases the risk of BC development. Conclusion: These
polymorphic gene variants and their associations may be considered as possible prognostic markers of BC development. The results
of analysis are different in total cohort and in subgroups distributed by age.
Key Words: breast cancer, renin-angiotensin system, polymorphism, gene.
Renin-angiotensin system �RAS� is represented
by the system of enzymes and hormones which reg�-
late arterial press�re� electrolytic and fl�id balance.
Renin-angiotensin cascade begins from secretion
of renin — aspartyl proteinase enzyme which �se
angiotensinogen �AGT� as a s�bstrate with the follow-
ing cleavage of angiotensin І. Then after hydrolysis
of angiotensin І by angiotensin I-converting enzyme
�АСЕ� there is generated angiotensin ІІ — octapeptide
hormone� potent vasoconstrictor and cell growth stim-
�lator. Biologic f�nctions of angiotensin ІІ are realized
�pon the binding with specific receptors. It has been
revealed that angiotensin II receptor type � �AT�R��
take part in realization of main estimated physiologic
and pathophysiologic f�nctions of angiotensin ІІ.
In many st�dies it has been shown that RAS activa-
tion directly or indirectly leads to activation of angiogen-
esis processes [�� �]. As far as cancer development�
progression and metastasis are associated with angio-
genesis and proliferative processes� one may s�ppose
that RAS co�ld be related to cancer development.
Recently there have been performed the st�d-
ies on the relation between genes coding for some
RAS components� and the risk of breast cancer �BC�
development [���]. However� s�ch st�dies mostly
have analyzed not more than two genes; none of s�ch
researches were performed in Ukraine.
Angiotensingen �AGT� gene is localized on long
arm of chromosome � in �q��-q�� loc�s and contains
� exons. Different genetic AGT variants determine
different physiologic activity of angiotensin ІІ. In AGT
gene there have been fo�nd more than �� differ-
ent polymorphic sites [6]� among which М���Т and
Т�7�М m�tations are the most st�died and clinically
significant. Т�7�М polymorphism �rs�76�� is char-
acterized by replacement of threonine to methionine
at position �7� of peptide chain ca�sed by single
n�cleotide replacement of cytosine to thymine at posi-
tion ��� of AGT gene �C���T�. М���Т polymorphism
�rs699� — replacement of threonine to methionine
at position ��� of peptide chain ca�sed by single
n�cleotide replacement of thymine to cytosine at posi-
tion 7�� of angiotensinоgen gene �Т7��С�. In Т-allele
carriers �with М���Т polymorphism� and M-allele car-
riers �with T�7�M polymorphism� the angiotensinоgen
level in blood is elevated compared to that in normalcy.
For example� with the �se of laboratory tests it has
been shown that in ���Т allele carriers� plasma level
of angiotensinоgen is by �����% higher than that
in normalcy [6]. In �99�� complete linkage of М���Т
and Т�7�М polymorphic variants has been shown [7].
The gene coding for angiotensin I-converting en-
zyme �ACE� is localized on long arm of chromosome
�7 in �7q�� loc�s and contains �6 exons and �� in-
trons. There are known more than ��� polymorphisms
in АСЕ gene� and the most st�died one is an insertion-
deletion �I/D� polymophism �rs�7997��� — the pres-
ence or lack of Al�-repeat ��8� bp large� in �6th intron.
Allele with Al�-repeat is named insertional one �І��
and allele lacking this repeat — deletional one �D�.
There has been fo�nd a strong association between
Received: December 13, 2012.
*Correspondence: E-mail — medgen@ukr.net
Abbreviations used: АСЕ — angiotensin converting enzyme;
AGT — angiotensinogen; AT2R1 — angiotensin II receptor type
1; BC — breast cancer; CG — control group; MDR — multifactor
dimensionality reduction; OR — odds ratio; PCR — polymerase
chain reaction; RFLP — restriction fragment length polymorphism;
RAS — renin-angiotensin system.
Exp Oncol ����
��� �� �������
��� Experimental Oncology ��� �������� ���� ���ne�
the gene polymorphic variant and ACE level in blood.
In a n�mber of st�dies it has been shown that ACE con-
tent in individ�als with DD genotype is approximately
twice higher than that in individ�als with ІІ genotype�
while intermediate blood level of this enzyme is fo�nd
in persons with ID genotype [8� 9]. Presently it remains
�nclear why polymorphism affects the level of sol�ble
АСЕ� b�t it co�ld be possible that genetic reg�lation
of АСЕ content occ�rs at transcription level. Some
a�thors s�ppose that insertion-deletion co�ld be re-
lated to altered transcription reg�lation and/or splicing
of АСЕ pre-mRNA [��� ��].
AT2R1 gene is localized on long arm of chromo-
some � in �q�� loc�s. There are known more than
twenty polymorphic variants of AT2R1 gene� and the
most st�died one is А��66С m�tation �replacement
of adenine to cytosine in ��66 position� in �’ �ntrans-
lated region. It has been shown that s�ch polymor-
phism is f�nctionally insignificant� b�t is tightly linked
with Т8��А variant which is localized in promoter part
of AT2R1 gene and affects transcription factor bind-
ing [��]. In individ�als with ��66С allele an elevated
sensitivity to angiotensin ІІ has been detected [��� ��].
The aim of o�r st�dy was to analyze the rela-
tion between polymorphic variants of AGT �T�7�M�
M���T�� ACE �I/D�� and AT2R1 �A��66C� genes and
their combinations and the risk of BC development
in Ukrainian women.
MATERIALS AND METHODS
The st�dy protocol was approved by the Bioethics
committee of SI “Instit�te of Genetic and Regenerative
Medicine of NAMS”� and written informed consent was
obtained from all participants.
��� female patients �average age — ��.��±��.99�
with histologically proven diagnosis of BC of stages
I and ІІ c�red in Kyiv City Oncology Center� were enrolled
in the st�dy. The control gro�p �CG� was composed
from ��� women �average age — �7.9�±��.�8� witho�t
cardiovasc�lar pathologies and cancer.
The BC patients were distrib�ted in three s�bgro�ps
according to the age of BC development: �� women
of yo�nger age� �8��� years old; �� women of middle
age� �6��� years old; �� women of postmenopa�sal
age� older than �� years. The control gro�p of women
was also distrib�ted in three s�bgro�ps dependent
on age �Table ��.
Table 1. Distribution of basic research groups into subgroups by age
Groups n Average age
18–35 years old
BC 53 30.6±3.96
CG 33 29.24±4.02
36–54 years old
BC 52 46.39±5.05
CG 23 45.87±5.78
Older than 54 years
BC 26 62.58±6.72
CG 46 62.22±6.75
Molec�lar-genetic st�dy was performed on the
samples of veno�s blood taken from all examined
patients and healthy controls. Genomic DNA was iso-
lated from veno�s blood with the �se of commercial
kit “DNA-Sorb-B” �CSRI of Epidemiology of Ministry
of Health of R�ssian Federation�.
Genotyping of I/D polymorphic variants of ACE
gene was carried o�t with the �se of allele-specific
PCR method� and analysis of polymorphic variants
of AGT gene �T�7�M� M���T�� and AT2R1 gene
�A��66C� was performed with the �se of PCR-RFLP
method according to protocols described in the lit-
erat�re [����8].
The res�lts were analyzed with the �se of Statistica
6.� program. To eval�ate the significance of the dif-
ferences between genotype freq�encies in compared
gro�ps� standard χ� Pearson criterion was �sed. Asso-
ciation of alleles or genotypes with BC predisposition
was eval�ated by odds ratio �OR�. Freq�encies of haplo-
types were calc�lated with the �se of “Tһe EH software
program” �EH� �Rockefeller University� USA�. Testing
of the differences in haplotype freq�ency distrib�tion
between gro�ps of patients and control gro�p was done
by algorithm proposed by X. Xie and �. Ott [�9]� and
realized in EH program. The differences p < �.�� were
considered statistically significant.
Inter-gene interactions were st�died with the �se
of bioinformative method of m�ltifactor dimensionality
red�ction �MDR� which allows modeling of genomic
interactions of high order what is impossible to perform
with the �se of conventional parametric methods. The
basis of the MDR method is a constr�ctive ind�ction
algorithm that converts two or more variables or attri-
b�tes to a single attrib�te. This process of constr�c-
ting a new attrib�te changes the representation space
of the data. The end goal is to create or discover a rep-
resentation that facilitates the detection of nonlinear
or nonadditive interactions among the attrib�tes s�ch
that prediction of the class variable is improved over
that of the original representation of the data. The
best model was determined among n-loc�s models
with the �se of perm�tation test which is realized
in MDRpt-�.�_beta_� program and was �sed for eval�-
ation of significance of these models.
RESULTS AND DISCUSSION
Distrib�tion of genotype freq�encies of the st�died
genes in the gro�p of BC patients and in control gro�p
is presented in Table �.
Table 2. Distribution of genotype frequencies of the studied genes
Gene, geno-
type
Frequency, n (%) χ2 OR (95% CI)BC (n = 131) CG (n = 102)
AGT T174M
174ТТ
174ТМ
174ММ
95 (72.52)
32 (24.43)
4 (3.05)
72 (75.49)
24 (23.53)
1 (0.98)
0.26
0.03
0.39
0.86 (0.47–1.55)
1.05 (0.57–1.93)
3.18 (0.35–28.91)
AGT M235T
235MM
235MT
235TT
36 (27.48)
66 (50.38)
29 (22.14)
32 (31.37)
55 (53.92)
15 (14.71)
0.42
0.29
2.07
0.83 (0.47–1.46)
0.87 (0.52–1.46)
1.65 (0.83–3.27)
ACE I/D
II
ID
DD
37 (28.24)
53 (40.46)
41 (31.30)
31 (30.39)
50 (49.02)
21 (20.56)
0.13
1.70
3.37
0.90 (0.51–1.59)
0.71 (0.42–1.19)
1.76 (0.96–3.22)
AT2R1 A1166C
1166AA
1166AC
1166CC
72 (64.96)
47 (35.88)
12 (9.160
64 (62.75)
24 (23.53)
14 (13.73)
1.43
4.13
1.21
0.72 (0.43–1.23)
1.82 (1.02–3.25)
0.63 (0.28–1.44)
Experimental Oncology ��� �������� ���� ���ne���� �������� ���� ���ne� ���ne� ���
Significant difference between BC gro�p and
CG has been revealed for ��66АС variant of AT2R1 gene
�χ�=�.��; OR=�.8�; 9�% CI �.����.��� what evi-
dences that the presence of this genotype in women
increases BC risk nearly �-fold. The res�lts of the st�dy
of S. Namazi et al. [��] have shown that ��66АС geno-
type is associated with higher TNM stage in BC patients.
According to literat�re data� �6 years are consi-
dered as a critical age for women beca�se exactly from
this age BC incidence q�ickly starts to rise. The large
n�mber of BC cases is diagnosed in �6��� years old
women. This co�ld be explained in part by initiation
of invol�tion changes in the str�ct�re of mammary
glands when gland�lar tiss�e is replaced by adipose
or fibro�s tiss�es that starts approximately at the age
of �6 years. Also� starting from �6 years in women
q�ick progression of fertility decrease begins� and
this process is ca�sed by hormonal changes: initially
imbalance develops� and then ac�te deficiency of sex
hormones — estrogens and progesterone.
An eval�ation of infl�ence of candidate gene poly-
morphism on the risk of BC development in different
age s�bgro�ps has been performed.
Analysis of distrib�tion of possible genotype vari-
ants in BC gro�p and control gro�p for each age
s�bgro�p has revealed significant differences only
for older s�bgro�ps b�t not for women of yo�nger
age �Table ��.
Table 3. Significant differences in the analysis of polymorphic and allele
variants of genes in age subgroups of BC patients and control group
Gene Polymor- Frequency, n (%) χ2 OR (95% CI)BC CG
36–54 years old
ACE (I/D) D allele 57 (54.81) 12 (26.09) 10.59 3.44 (1.60–7.37)
Older than 54 years
AGT (M235T) 235TT 11 (42.31) 7 (15.22) 5.14 4.09 (1.33–12.51)
AT2R1 (A1166C) 1166AC 12 (46.15) 10 (21.74) 4.67 3.09 (1.09–8.75)
For age s�bgro�p � ��6��� years� the presence
of D allele of AСЕ gene elevates the risk of BC deve-
lopment� what is in accordance with the data of other
a�thors [�� ��]. W.P. Koh et al. cond�cted a st�dy
among Chinese postmenopa�sal women in which
they fo�nd that individ�als carrying the II genotype
had a significantly red�ced risk of BC independently
of environmental and other familial risk factors for the
disease [��]. On other hand� A. Yaren et al. showed
that DD genotype may infl�ence the local t�mor growth
of BC in premenopa�sal patients [��].
For women older than �� years s�ch associations
disappear and the risk of BC development is increased
in the presence of ���ТТ genotype of AGT gene
�OR=�.�9; 9�% CI �.�����.���� and in the presence
of ��66АС genotype of AT2R1 gene �OR=�.�9; 9�%
CI �.�9�8.7�� compared to control gro�p. Contrary�
A.M. González-Z�loeta Ladd et al. showed that post-
menopa�sal women who were homozygo�s for the
���M allele of the M���T AGT polymorphism had
a significantly increased risk for BC [�]. The res�lts
of other st�dy showed that A��66C was associated
with a lower risk of BC for ��66C carriers [��].
At the next stage of the work we have analyzed the
infl�ence of combinations of the st�died polymorphic
variants of ACE� AGT� AT2R1 genes on BC risk in three
age s�bgro�ps of the BC patients and control gro�p
�Table ��. Significant differences have been revealed
only for two older aged s�bgro�ps b�t not in yo�nger
one ��8��� years�.
From the data of this Table one may concl�de
that in gro�p � ��6��� years old women� combina-
tion of genotypes ACE II/AGT �7�TT is associated
with highly significant protective effect in BC deve-
lopment. However� if in this genotype combination
polymorphic variant II of ACE gene is replaced by DD�
the risk of BC development increases. These facts al-
low to s�ppose that an impact of polymorphic variant
I/D of АСЕ gene in BC development is more potent
than protective effect of genotype �7�ТТ of AGT gene.
In the oldest age gro�p of women �> �� years�
genotype ���ТТ of AGT gene has the strongest impact
in the risk of BC development �see Tables � and ��. This
risk elevates in the presence of combined genotypes
AGT ���ТТ/AGT �7�ТМ — from �.�9 fold to �.�8 fold�
and �p to �.67 fold in the presence of combination AGT
���ТТ/AT2R1 ��66AA. Why do genotypes ���ТТ and
�7�ТМ of AGT gene which are responsible for elevated
level of angiotensinogen� increase the risk of BC deve-
lopment? It is known that high AGT levels are capable
to decrease angiogenesis and s�ppress t�mor growth.
This co�ld be explained by the low degree of estrogens
in females at postmenopa�sal period — estrogens may
reg�late angiotensinogen expression and affect its level.
Table 4. The genotype combinations which affect BC risk in the studied
age subgroups
Genes Genotype
combination BC, n (%) CG, n (%) χ2 OR (95% CI)
From 36 to 54 years
ACE (I/D), AGT
(M235T)
II/235MT 6 (11.54) 8 (34.78) 4.25 0.24
(0.07–0.82)
ACE (I/D), AGT
(T174M)
II/174TT 11 (21.15) 11 (47.83) 5.47 0.29
(0.10–0.84)
ACE (I/D), AGT
(T174M)
DD/174TT 16 (30.77) 0 (0.00) 7.26 -
Older than 54 years
AGT (M235T),
AGT (T174M)
235ТТ/174TМ 7 (26.92) 3 (6.52) 4.20 5.28
(1.23–22.65)
AGT (M235T),
AT2R1 (A1166C)
235ТТ/1166AA 8 (30.77) 4 (8.70) 4.35 4.67
(1.25–17.49)
At the next stage of o�r st�dy we have calc�lated the
freq�encies of haplotypes of AGT gene �� possible vari-
ants of haplotypes� in age s�bgro�ps of women with the
�se of EH program. The analysis of calc�lated haplotype
freq�encies did not reveal significant differences between
st�died age s�bgro�ps of BC patients and control gro�p.
Also we have performed a modeling of interaction
between st�died genes in BC patients with the �se
of MDR method which allows perform sim�ltaneo�s
analysis of many polymorphic gene variants selecting
combinations with the highest pathogenetic signifi-
cance. For eval�ation of interactions between polymor-
phic gene variants with the �se of MDR method we have
�sed exha�stive search algorithm which eval�ates all
possible combinations of the st�died DNA-markers
in relation to the risk of BC development �Table ��.
��� Experimental Oncology ��� �������� ���� ���ne�
Table 5. Models for interlocus interactions of candidate BC genes in women
calculated with the use of MDR program at integrated search regimen
Num-
ber of loci
in a model
Combination of loci in a model
Cross-vali-
dation con-
sistency, %
Testing bal-
ancing accu-
racy, %
From 18 to 35 years
2 ACE (I/D)/AT2R1 (A1166C) 90 50.29
From 36 to 54 years
2* ACE (I/D)/AGT (M235T) 100 78.09
4 ACE (I/D)/AT2R1 (A1166C)/
AGT (T174M)/AGT (M235T)
100 60.95
Older than 54 years
2 AT2R1 (A1166C)/AGT (M235T) 100 67.47
*The best model (р = 0.05) among n-locus models tested in 1000 simula-
tions with the use of MDRpt-1.0_beta_2 program.
Among proposed models of inter-gene interac-
tions in BC patients from three age s�bgro�ps only
one model get thro�gh perm�tation test — two-loc�s
model of ACE �I/D�/AGT �M���T� interaction� which
is characterized by ���% reprod�cibility and 78.�9%
precognition acc�racy. This model correctly predicted
in 69% cases probability of occ�rrence of BC devel-
opment and in 7�% cases correctly classified healthy
women from �6 to �� years old.
An analysis of obtained data allows �s to concl�de
that the character of interactions of polymorphic
variants of ACE �I/D� and AGT �M���T� genes in age
s�bgro�p from �6 to �� years possesses an expressed
synergic effect in BC development — AGT �M���T�
enhanced the action of ACE �I/D� by 9.�9%.
In concl�sion o�r st�dy has shown that polymor-
phic variants of RAS genes and their associations
may be considered as possible prognostic markers
of BC risk; the res�lts of analysis are different for
general cohort and s�bgro�ps distrib�ted by age�
that’s why in s�ch st�dies one sho�ld take into acco�nt
patient’s age as an important parameter.
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