Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis
The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vascular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations of functional VEGF −2578C>A, −63...
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| Cite this: | Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis / E.V. Krupnova, M.N. Shapetska, E.P. Mikhalenko, N.V. Chebotaryova, A.N. Shchayuk, S.N. Pissarchik, A.V. Prokhorov // Experimental Oncology. — 2015. — Т. 37, № 3. — С. 213-217. — Бібліогр.: 38 назв. — англ. |
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Krupnova, E.V. Shapetska, M.N. Mikhalenko, E.P. Chebotaryova, N.V. Shchayuk, A.N. Pissarchik, S.N. Prokhorov, A.V. 2019-01-22T19:49:12Z 2019-01-22T19:49:12Z 2015 Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis / E.V. Krupnova, M.N. Shapetska, E.P. Mikhalenko, N.V. Chebotaryova, A.N. Shchayuk, S.N. Pissarchik, A.V. Prokhorov // Experimental Oncology. — 2015. — Т. 37, № 3. — С. 213-217. — Бібліогр.: 38 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145534 The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vascular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations of functional VEGF −2578C>A, −634G>C, and +936C>T polymorphisms with the risk for occurrence and progression of non-small cell lung cancer (NSCLC) in patients living in Republic of Belarus. Materials and Methods: A total of 202 patients (147 males and 55 females) diagnosed as having the NSCLC. The control group consisted of 336 individuals (245 males and 91 females) without an oncopathology. The total DNA was isolated from peripheral blood. We investigated the single nucleotide polymorphisms of VEGF (rs 2010963), (rs 699947), (rs 3025039). The genotyping was performed by PCR-RFLP analysis. Results: Our results revealed a marginally significant association of the –2578CC genotype (p=0.002) with a greater degree of tumor spread (Т2–Т4). Heterozygous genotypes –2578СА and +936СT carriers were included into the follow-up group significantly more often (р=0.021 and р=0.012, respectively). Our study demonstrate that VEGF –2578A/C and +936C/T polymorphisms are among the factors determining the individual peculiarities of NSCLC course in this population and can be used for clarifying the prognosis of the disease. Key Words: vascular endothelial growth factor, polymorphism, non-small cell lung cancer. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis Article published earlier |
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Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis |
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Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis Krupnova, E.V. Shapetska, M.N. Mikhalenko, E.P. Chebotaryova, N.V. Shchayuk, A.N. Pissarchik, S.N. Prokhorov, A.V. Original contributions |
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Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis |
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Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis |
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Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis |
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Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis |
| title_sort |
role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis |
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Krupnova, E.V. Shapetska, M.N. Mikhalenko, E.P. Chebotaryova, N.V. Shchayuk, A.N. Pissarchik, S.N. Prokhorov, A.V. |
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Krupnova, E.V. Shapetska, M.N. Mikhalenko, E.P. Chebotaryova, N.V. Shchayuk, A.N. Pissarchik, S.N. Prokhorov, A.V. |
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Original contributions |
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2015 |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vascular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations of functional VEGF −2578C>A, −634G>C, and +936C>T polymorphisms with the risk for occurrence and progression of non-small cell lung cancer (NSCLC) in patients living in Republic of Belarus. Materials and Methods: A total of 202 patients (147 males and 55 females) diagnosed as having the NSCLC. The control group consisted of 336 individuals (245 males and 91 females) without an oncopathology. The total DNA was isolated from peripheral blood. We investigated the single nucleotide polymorphisms of VEGF (rs 2010963), (rs 699947), (rs 3025039). The genotyping was performed by PCR-RFLP analysis. Results: Our results revealed a marginally significant association of the –2578CC genotype (p=0.002) with a greater degree of tumor spread (Т2–Т4). Heterozygous genotypes –2578СА and +936СT carriers were included into the follow-up group significantly more often (р=0.021 and р=0.012, respectively). Our study demonstrate that VEGF –2578A/C and +936C/T polymorphisms are among the factors determining the individual peculiarities of NSCLC course in this population and can be used for clarifying the prognosis of the disease. Key Words: vascular endothelial growth factor, polymorphism, non-small cell lung cancer.
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1812-9269 |
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https://nasplib.isofts.kiev.ua/handle/123456789/145534 |
| citation_txt |
Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis / E.V. Krupnova, M.N. Shapetska, E.P. Mikhalenko, N.V. Chebotaryova, A.N. Shchayuk, S.N. Pissarchik, A.V. Prokhorov // Experimental Oncology. — 2015. — Т. 37, № 3. — С. 213-217. — Бібліогр.: 38 назв. — англ. |
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2025-11-24T20:37:53Z |
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1850492878181105664 |
| fulltext |
Experimental Oncology 37, 213–217, 2015 (September) 213
ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR
IN NON-SMALL CELL LUNG CANCER PATHOGENESIS
E.V. Krupnova1,*, M.N. Shapetska2, E.P. Mikhalenko1, N.V. Chebotaryova1,
A.N. Shchayuk1, S.N. Pissarchik3, A.V. Prokhorov2
1Institute of Genetics and Cytology, NAS of Belarus, Minsk 220072, Republic of Belarus
2Belarusian State Medical University, Minsk 220116, Republic of Belarus
3City Clinical Pathologoanatomic Bureau, Minsk 220116, Republic of Belarus
The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vas-
cular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations
of functional VEGF −2578C>A, −634G>C, and +936C>T polymorphisms with the risk for occurrence and progression of non-small
cell lung cancer (NSCLC) in patients living in Republic of Belarus. Materials and Methods: A total of 202 patients (147 males and
55 females) diagnosed as having the NSCLC. The control group consisted of 336 individuals (245 males and 91 females) without
an oncopathology. The total DNA was isolated from peripheral blood. We investigated the single nucleotide polymorphisms of VEGF
(rs 2010963), (rs 699947), (rs 3025039). The genotyping was performed by PCR-RFLP analysis. Results: Our results revealed
a marginally significant association of the –2578CC genotype (p=0.002) with a greater degree of tumor spread (Т2–Т4). Heterozy-
gous genotypes –2578СА and +936СT carriers were included into the follow-up group significantly more often (р=0.021 and р=0.012,
respectively). Our study demonstrate that VEGF –2578A/C and +936C/T polymorphisms are among the factors determining the in-
dividual peculiarities of NSCLC course in this population and can be used for clarifying the prognosis of the disease.
Key Words: vascular endothelial growth factor, polymorphism, non-small cell lung cancer.
The angiogenesis is an important process in the pa-
t hogenesis of malignancies. It is regulated by various
growth factors, with the vascular endothelial growth
factor (VEGF-A or VEGF) playing the central role [1].
The VEGF gene expression is closely related to the de-
gree of vascularization and the prognosis for the oc-
currence of numerous solid tumors and is considered
to be a predictor of resistance to the chemo- and ra-
diotherapy [2]. An elevated VEGF expression is associ-
ated with tumor growth and metastatic process, while
the inhibited VEGF expression results in suppressed
tumor growth [3].
The VEGF gene also triggers the activation of the pro-
tease cascade involved in the degradation of extracellular
matrix, suppressing apoptosis, stimulates the endothelial
cells survival, increases vascular permeability, inhibits
the dendritic cells differentiation, regulates the hexose
transport in endothelial cells as well as activates tissue
factors and monocytes migration [1]. Clinical studies
have shown that the high level of VEGF expression and,
respectively, the increased number of microvessels
in the tumor correlate with the disease stage and the un-
favorable prognosis for many tumor types, including
the non-small cell lung cancer (NSCLC) [4–8].
The VEGF gene is located on the short arm
of chromosome 6 (6p21.3) and consists of eight
exons and seven introns [7]. VEGF is a diametric
glycoprotein, acting via tyrosine kinase receptors
VEGFR1 and VEGFR2 located predominantly on en-
dothelial cells [9].
Polymorphic sites of VEGF gene determining the level
of VEGF production are found in the promoter — 5´-un-
translated region (5´-UTR) as well as in 5´- and 3´-un-
translated regions of the gene (3´-UTR).
The VEGF gene polymorphism is associated with
differentiated VEGF expression and protein produc-
tion. VEGF-2578C/C, −634 C/-genotypes are related
to high level of VEGF expression [5, 9–12], while +936T
allele correlates with low VEGF expression and its low
levels in blood plasma [13, 14].
Recent studies show that individual polymorphic
variants of VEGF influence the development of cer-
tain cancers. In particular, VEGF C-634G, C-2578A,
C+936T polymorphisms are associated with an in-
creased lung cancer risk in Asian population [15]. Based
on the above-mentioned, it can be assumed that these
single nucleotide substitutions of the VEGF gene related
to angiogenesis can affect the risk of tumour occur-
rence and progression as well as the patients’ survival.
The aim of the present study was to evaluate pos-
sible associations of functional VEGF −2578C>A,
−634G>C, and +936C>T polymorphisms with the risk
for occurrence and progression of NSCLC in patients
living in the territory of the Republic of Belarus.
MATERIALS AND METHODS
202 patients (147 males and 55 females) diag-
nosed as having the NSCLC and treated at the Minsk
City Oncology Dispensary during the period from
2003 to 2012 were included in the study. The control
group consisted of 336 individuals (245 males and
91 females) without an oncopathology who were age-,
gender- and comorbidity matched with NSCLC pa-
Submitted: January 20, 2015.
*Correspondence: E-mail: ekrupnova@inbox.ru
Fax: (+375 17) 284-19-17
Abbreviations used: 3´-UTR — 3´-untranslated region; 5´-UTR —
5´-untranslated region; NSCLC — non-small cell lung cancer;
VEGF — vascular endothelial growth factor.
Exp Oncol 2015
37, 3, 213–217
214 Experimental Oncology 37, 213–217, 2015 (September)
tients. Clinical characteristics of patients with NSCLC
and controls are presented in Table 1.
Table 1. Characteristics of study population
Characteristics
Patients with NSCLC
(n = 202)
Controls
(n = 336)
n (%) n (%)
Gender:
female 55 (27.2) 91 (27.1)
male 147 (72.8) 245 (72.9)
Smoking status:
smokes 67 (33.2) 201 (59.8)
does not smoke 119 (58.9) 135 (40.2)
no information 16 (7.9) −
Stage:
I 108 (53.5) −
II 27 (13.4) −
III 55 (27.2) −
IV 12 (5.9) −
Histology:
squamous-cell carcinoma 106 (52.5) −
adenocarcinoma 96 (47.5) −
Surgery:
lobectomy/bilobectomy 121 (65.1) −
pneumonectomy 42 (22.6) −
lung resection 13 (7.0) −
biopsy 10 (5.4) −
Therapy:
chemotherapy 65 (32.2) −
radiotherapy 39 (19.3) −
no therapy 98 (48.5) −
The study was performed in compliance with
the principles of voluntary participation and confiden-
tiality, in accordance with the questioning of patients
and the approval from the local Ethics Committee
to study tissue samples and biological fluids.
The diagnosis of lung cancer in patients has been
established on the basis of clinical signs of the disease,
history data, bronchoscopy, X-ray examination and
computed tomography, cytomorphology of sputum
and tumour tissue biopsies. In the group of NSCLC
patients, the mean age was 61.6±0.6, in the control
group — 61.6±0.8 years.
All cases of lung malignancies have been identi-
fied according to the International Classification
TNM/pTNM (7th edition, 2009). The histological
type of lung carcinoma was determined according
to the WHO histological criteria (3rd edition, 1999).
The group of NSCLC included the most common
neoplasms — squamous-cell carcinoma and ade-
nocarcinoma. The treatment was mostly surgical:
lobectomy — 65.1%, pneumonectomy — 22.6%,
lung resection — 7.0%. Only a biopsy was performed
in 5.4% of cases, and in 7.9% of patients the operation
was not done because of the process spread or severe
comorbidity.
The total DNA from the peripheral blood was
isolated using the Mathew method [16]. VEGF
C-634G (rs 2010963), C-2578A (rs 699947), C+936T
(rs 3025039) polymorphisms were genotyped
by the polymerase chain reaction method and the re-
striction fragment length polymorphism analysis (PCR-
RFLP analysis) using specific primers and restriction
endonucleases [15, 17]. Primers for the analysis were
synthesized by “Primetekh”, Minsk. The reagents for
PCR and PCR-RFLP were manufactured by “Fermen-
tas”, Vilnius.
Statistical analysis. Statistical analyses were per-
formed using Excel and Statistica 7.0. When compa-
ring genotype frequencies, Pearson’s chi-squared test
(χ2) was used. The association between the genotypes
and the disease course was assessed by the value
of odds ratio (OR).
RESULTS AND DISCUSSION
An elevated VEGF expression was revealed
while studying the variety of malignancies: cancers
of the colon, rectum, liver, lung, thyroid, digestive
tract; breast, kidney and bladder adenocarcinoma;
ovary and uterus carcinoma; angiosarcoma, multi-
form glioblastoma [18–21]. In turn, the level of VEGF
expression depends largely on the polymorphic vari-
ants of the gene.
Therefore, the first phase of our work was to analy-
ses the association between VEGF C-634G, C-2578A
and C+936T polymorphisms and the risk of NSCLC.
The analysis of data on VEGF genotyping in patients
with NSCLC and controls is presented in Table 2.
Frequency distribution of alleles and genotypes
of functionally significant VEGF polymorphisms
in the population of patients living in the territory
of the Republic of Belarus was close to the occur-
rence of the same polymorphisms in the control group.
Statistically significant differences in the frequency
of the studied genotypes between the group of pa-
tients with NSCLC and the control group were not
39. Schultz A, Lavie L, Hochberg I, et al. Interindividual heterogeneity in the hypoxic regulation of VEGF: significance
for the development of the coronary artery collateral circulation. Circulation 1999; 100: 547–52.
Experimental Oncology 37, 213–217, 2015 (September) 215
found. Similar results on the frequency of the studied
VEGF single nucleotide substitutions were obtained for
the populations in Germany and Sweden.
Based on the results, it can be assumed that there
is no connection between the studied VEGF polymor-
phisms and the risk of NSCLC in this population.
Since VEGF is a major mediator of angiogenesis,
it can be supposed that VEGF С-634G, C-2578A and
C+936T polymorphisms will rather affect the pheno-
type and tumor biological behavior than the risk for
tumor occurrence.
The next stage of our study was to find the relation-
ship between the polymorphisms under study and
the clinical course of this disease. The comparative
analysis of genotypes distribution of three functionally
significant VEGF polymorphisms and tumor size, me-
tastasis and clinical outcomes in the group of patients
with NSCLC has been carried out.
VEGF triggers the neoplastic angiogenesis, resulting
in increased microvascular density, and malignant tis-
sue receives more nutrients [23, 24]. VEGF secretion
by tumor cells leads to the synthesis of proangiogenic
factors. The newly formed vessels begin to supply
malignant tissue with oxygen and nutrients; the tumor
is growing and producing more VEGF. VEGF increases
the level of VEGFR2 receptor expression by endothe-
liocytes of tumor microvessels, thus stimulating the cell
growth and endothelial cells proliferation [25].
Structurally and functionally the neoplastic vessels
differ from the normal ones, with high permeability,
chaotic branching, multiple loops, weaves, dead-end
branches, lack of structured vasculature being typical
for them [2]. Chaotic arrangement of tumor vessels
results in uneven oxygen supply to the surrounding
tissues, formation of local hypoxic foci, and is followed
by tumor resistance to the radio-and chemotherapy.
With an elevated VEGF expression, the vascular
permeability increases leading to a higher interstitial
and intratumoural pressure, facilitating the penetration
of tumor cells into the bloodstream [26].
The relationship between the tumor angiogenesis
level, tumor size and metastatic process is confirmed
by the correlation between the course of the disease
and microvascular density of the primary tumor [27–
32]. Different VEGF polymorphisms are associated
with lymphogenic and hematogenous metastases
in a variety of malignancies [28, 29].
The performed analysis of the relationships be-
tween three VEGF gene polymorphisms and tumor size
(Table 3) has shown that genotype –2578СС carriers
displayed a greater degree of tumor spread (Т2–4) sig-
nificantly more frequently (р = 0,002) compared to the
primary focus spread (Т1). On the contrary, the carri-
ers of –2578СА genotype more often presented with
small non-invasive cancer (Т1). However, in this group
of NSCLC patients, no statistically significant associa-
tions between the studied polymorphic allele variants
and regional and/or distant metastases were found
(Table 4).
The in vitro studies conducted by M. Moham-
madi and M.С. Shahbazi has shown that -2578C allele
correlated with higher VEGF expression compared
to A allele [30, 31]. Similar results were obtained
by M. Perrot-Applanat who proved that –2578С allele
was associated with an elevated VEGF expression and
pointed to the possible involvement of VEGF proteins
in the autocrine regulation of the tumor growth [32].
Perhaps, this is likely to explain our findings, where
the homozygous carriers (–2578СС) had higher degree
of the tumor spread. The lower level of VEGF expres-
sion in the presence of –2578А allele seems to have
a protective effect in heterozygous carriers (–2578СА)
associated with a lesser degree of the neoplasm spread.
In the population under study, a significant rela-
tionship between the –2578СА variant and the degree
of spread of the primary tumor as well as the outcome
of the disease was detected (Table 5). Heterozy-
Table 2. Frequency distribution of polymorphic variants of VEGF in patients with NSCLC and control groups in different populations
Genotype Belarus (original data) Germany [22] Sweden [22]
Patients Controls OR (95% CI) Patients Controls OR (95% CI) Patients Controls OR (95% CI)VEGF (G634C) N=186; n (%) N=364; n (%) N, % N, % N=936; n (%) N=941; n (%)
GG 83 (44.6) 186 (51.1) 0.77 (0.54–1.10) − − − 488 (52.1) 492 (52.3) 1.00
GC 88 (47.3) 154 (42.3) 1.22 (0.86–1.75) − − − 363 (38.8) 367 (39.0) 1.00 (0.82–1.21)
CC 15 (8.1) 24 (6.6) 1.24 (0.64–2.43) − − − 85 (9.1) 82 (8.7) 1.05 (0.74–1.47)
G allele 254 (68.3) 526 (72.3) 0.83 (0.63–1.09) − − − 1339 (71.5) 1351 (72.0) 0.99 (0.86–1.14)
С allele 118 (31.8) 202 (27.7) 1.21 (0.92–1.59) − − − 533 (28.5) 531 (28.0) 1.01 (0.86–1.17)
VEGF (С2578А) N=162; n (%) N=360; n (%) N=153; n (%) N=162; n (%) N=939; n (%) N=940; n (%)
СС 41 (25.3) 83 (23.0) 1.13 (0.74–1.74) 44 (28.8) 50 (30.9) 1.00 258 (27.5) 257 (27.3) 1.00
СА 90 (55.6) 186 (51.7) 1.17 (0.81–1.70) 75 (49.0) 72 (44.4) 1.18 (0.68–2.06) 449 (47.8) 451 (48.0) 0.99 (0.79–1.24)
АА 31 (19.1) 91 (25.3) 0.70 (0.44–1.11) 34 (22.2) 40 (24.7) 0.97 (0.50–1.86) 232 (24.7) 232 (24.7) 1.00 (0.82–1.23)
C allele 172 (53.1) 352 (48.9) 1.18 (0.91–1.54) 163 (53.3) 172 (53.1) 1.01 (0.74–1.38) 965 (51.4) 965 (51.2) 0.78 (0.68–0.89)
A allele 152 (46.9) 368 (51.1) 0.85 (0.65–1.10) 143 (46.7) 152 (46.9) 0.99 (0.73–1.36) 913 (48.6) 915 (48.8) 1.05 (0.93–1.20)
VEGF (С936T) N=161; n (%) N=360; n (%) N=153; n (%) N=163; n (%) N=924; n (%) N=934; n (%)
CC 115 (71.4) 267 (74.2) 0.87 (0.57–1.32) 120 (78.4) 128 (78.5) 1.00 708 (76.6) 720 (77.1) 1.00
CT 38 (23.6) 80 (22.2) 1.08 (0.70–1.68) 31 (20.3) 31 (19.0) 1.07 (0.59–0.93) 204 (22.1) 203 (21.7) 1.02 (0.81–1.28)
TT 8 (5.0) 13 (3.6) 1.40 (0.57–3.44) 2 (1.3) 4 (2.5) 0.53 (0.07–3.46) 12 (1.3) 11 (1.2) 1.11 (0.45–2.71)
С allele 268 (83.2) 614 (85.3) 0.86 (0.60–1.23) 271 (59.8) 287 (88.0) 0.20 (0.14–0.30) 1620 (87.7) 1643 (88.0) 0.97 (0.80–1.18)
T allele 54 (16.8) 106 (14.7) 1.17 (0.82–1.67) 182 (40.2) 39 (12.0) 4.94 (3.37–7.25) 228 (12.3) 225 (12.0) 1.03 (0.84–1.25)
Table 3. Distribution of frequencies of polymorphic variants of VEGF and tumor size in patients with NSCLC
Tumour
size N
G634C
N
C2578A
N
C936T
GG GC CC CC CA AA CC CT TT
n % n % n % n % n % n % n % n % n %
T1 70 32 45.7 33 47.1 5 7.1 57 6 10.5* 40 70.2** 11 19.3 41 29 70.7 11 26.8 1 2.4
216 Experimental Oncology 37, 213–217, 2015 (September)
gous genotype –2578СА carriers were included into
the follow-up group significantly more often (р = 0.021).
It should be noted that a similar results was observed
for another VEGF polymorphism — the heterozygous
variant +936СT located in the 3´-UTR (р = 0.012). More-
over, C. Oliveira et al. have shown that heterozygous
+936СT genotype was increasingly associated with
a non-recurrent disease [11]. No associations between
the VEGF –634G>C polymorphism and the survival
of patients with NSCLC have been found.
It has been demonstrated that the polymorphism
of a single nucleotide located in the promoter region
or 3´- and 5´-UTR affects the protein expression
at the transcriptional level [33]. Initially, the hypoxia
induced factor (HIF-1) joins VEGF gene in the pro-
moter region (–2578СА polymorphism) and increases
its expression. Gene polymorphism in this region can
weaken or strengthen this interaction, and, therefore,
alter the VEGF expression (–2578СА) [34] that, in turn,
will affect the formation and permeability of microves-
sels and, finally, the tumor size, metastasis and survival.
Based on the results of the study on the correla-
tion between the polymorphisms and development
of the di sease in this population, it has been estab-
lished that the carriers of –2578СС genotype displayed
a greater degree of tumor spread (Т2–4) significantly
more often (р = 0.002) while the carriers of –2578СА
genotype presented with small non-invasive can-
cers (Т1) more frequently (р = 0.021). The carriers of
–2578C/A genotype were significantly often observed
(р = 0.021) in the “follow-up” group. Given that the high
level of VEGF expression is related to an increased risk
of a recurrent disease and shorter survival of subjects
with different cancers [35], one may suggest the VEGF
(–2578С/-) genotype to contribute to the high expression
of the corresponding protein product in the development
of NSCLC.
The mechanism of most associations between single
nucleotide substitutions and clinical behavior of tumors
is still largely unclear. It should be taken into account
that 5´- and 3´-UTR contain key regulatory elements
sensitive to hypoxia [36–38] and contribute to high
variability of VEGF production [39]. For instance, VEGF-
634G>C and –2578A>C polymorphisms in the 5´-UTR
affect the efficiency of protein translation [33], and
936C>T polymorphism in the 3´-UTR influences the VEGF
circulating plasma concentrations [13] and tumor tissue
expression of VEGF [5]. This can explain the protective ef-
fect of the VEGF +936T allele in breast cancer metastasis
(due to the reduced VEGF expression) [4, 11].
Thus, the results of our study demonstrate that
VEGF –2578A/C and +936C/T polymorphisms are
among the factors determining the individual pecu-
liarities of NSCLC course in this population and can
be used for clarifying the prognosis of the disease.
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