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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 942-948

Vascular endothelial growth factor gene polymorphism in Egyptian patients with B-cell chronic lymphocytic leukemia


1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia Governorate, Egypt
2 Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia Governorate, Egypt
3 Shebin El-Kom Teaching Hospital, Shebin El-Kom, Menoufia Governorate, Egypt

Date of Submission27-Mar-2019
Date of Decision17-May-2019
Date of Acceptance20-May-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
Soha A. K. Zanaty
Shebin El Kom 32511, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_132_19

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  Abstract 


Objective
The objective of this study was to add to the scope of the role of vascular endothelial growth factor (VEGF) +936C/T gene polymorphism in the prognosis of B-cell chronic lymphocytic leukemia (CLL) in Egyptian patients.
Background
CLL is a common lymphoid malignancy that has a highly variable clinical course. Several studies have targeted to determine the high risk of disease progression; VEGF-mediated angiogenesis is one of the most vital regulators of angiogenesis and vascular permeability, which can contribute to the pathogenesis of B-CLL.
Patients and methods
This prospective case–control study was conducted on 30 patients of CLL and 20 age-matched and sex-matched healthy individuals as a control group from January 2016 to January 2018. All patients were subjected to full history taking, clinical examination, and laboratory investigations. Genotyping of VEGF + 936C/T (rs3025039) single nucleotide polymorphism was done using PCR-restriction fragment length polymorphism method.
Results
VEGF + 936C/T gene polymorphism showed no statistically significant differences in the distribution of the genotypes and allele frequencies between patients and controls. No significant relation was found between genotype distribution and sex, age, somatic hypermutation, hemoglobin, total leukocytic count, and absolute lymphocytes; however, TT genotype and recessive genetic model (CT + CC) revealed a significant relationship with the platelet count in patients with CLL (P = 0.014). A statistically significant relationship was depicted between TT genotype and recessive genetic model (CT + CC) and poor prognostic markers such as lactate dehydrogenase, β2 microglobulin, and modified Rai staging system (IV).
Conclusion
VEGF + 936C/T gene polymorphism can predict poor prognosis in patients with CLL.

Keywords: +936C/T, angiogenesis, chronic lymphocytic leukemia, restriction fragment length polymorphism, vascular endothelial growth factor


How to cite this article:
Ahmedy IA, Soliman MA, Elkhouly EA, Zanaty SA, El-Din RI. Vascular endothelial growth factor gene polymorphism in Egyptian patients with B-cell chronic lymphocytic leukemia. Menoufia Med J 2020;33:942-8

How to cite this URL:
Ahmedy IA, Soliman MA, Elkhouly EA, Zanaty SA, El-Din RI. Vascular endothelial growth factor gene polymorphism in Egyptian patients with B-cell chronic lymphocytic leukemia. Menoufia Med J [serial online] 2020 [cited 2020 Oct 28];33:942-8. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/942/296648




  Introduction Top


Chronic lymphocytic leukemia (CLL) is the most common adult leukemia type characterized by proliferation and gathering of morphologically matured lymphocytes in the peripheral blood, bone marrow, and lymphoid tissues [1].

The precise pathogenesis of CLL is still unknown. However genetic, environmental, and immunological factors have been offered to account for the development of CLL. Patients with CLL present with a highly variable clinical course, with overall survival ranging from months to decades, which reflects the biological diversity of the disease [2].

Angiogenesis is a sequence of different processes that start with the dilation in pre-existing vessels followed by the proliferation of endothelial cells, development of new blood vessels, and recruitment of the perivascular cells. Therefore, angiogenesis is a key factor in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) is one of the growth factors that are well known for controlling the angiogenesis process [3].

Pathological angiogenesis is stated to play an essential role within the progression of a solid as well as hematological malignancy, including CLL [4]. There are several studies examining the association between VEGF genotypes and human diseases as well as solid tumors [5].

VEGF is a cytokine that has a potent angiogenic and vascular permeabilityenhancing activity [6]. VEGF gene is highly polymorphic, and its promoter, 5'-untranslated region (UTR), and 3'-UTR, has a variety of single-nucleotide polymorphisms (SNPs). VEGF SNPs in the 3'-UTR have been found to be associated with variations in VEGF protein production. These SNPs could result in high expression of the VEGF gene and increase tumor-related angiogenesis and metastasis, playing a key role in a series of pathologic processes involved in tumor growth and metastasis [7].

One of the important SNPs that have been studied is + 936C/T, which is located in the 3'-UTR of VEGF gene [8]. The role of + 936C/T polymorphism was well studied in solid tumors, but very few studies are reported in leukemia [9].

This is the first study to analyze the relationship between the VEGF + 936C/T gene polymorphism and risk of B-cell chronic lymphocytic leukemia (B-CLL) in an Egyptian population.

The aim of this study was to add to the scope of the role of VEGF + 936C/T gene polymorphism in the prognosis of B-CLL in Egyptian patients.


  Patients and Methods Top


This prospective case–control study was carried out at the Clinical Pathology and Oncology Departments, Faculty of Medicine, Menoufia University, from January 2016 to January 2018. The study was approved by the Ethics Committee of the Faculty of Medicine, Menoufia University. Written informed consent was obtained from all patients and control individuals. This study included 30 patients with CLL (24 males and six females), with age ranging from 42 to 72 years, and 20 age-matched and sex-matched healthy individuals as a control group (16 males and four females), with age ranging from 40 to 68 years. All individuals were subjected to clinical history taking, full physical examination, and abdominal, pelvic, and chest computed tomographic scans for detection of internal organs or lymph node involvement. Cases with persistent lymphocytosis of at least 5 × 109/l in the peripheral blood, with blood film showing characteristically small, mature-looking lymphocytes and smudge cells, were further investigated to confirm diagnosis of CLL and to assess the tumor burden and prognosis by repetition of complete blood count (CBC) and blood film, and immunophenotypic scoring system (CD5, CD23, FMC7, CD22, and surface membrane immunoglobulin). CBC was performed using XT-1800i hematology analyzer (SYSMEX, Kobe, Japan). Peripheral blood film was performed. Immunophenotypic scoring system was measured by FACS caliber flow cytometer (BD immune-cytometry systems; BD Bioscience, San Jose, California, USA). Serum level of lactate dehydrogenase (LDH) was determined using Beckman AU480 Chemistry Analyzer (Beckman Instruments Inc., Carlsbad, California, USA). Serum level of β2 microglobulin was determined using Microparticle Enzyme Immunoassay technology on Cobas 6000 Analyzer (Roche Diagnostics, Indianapolis, Indiana, USA). Molecular testing for VEGF + 936C/T gene polymorphism was performed by PCR on the basis of restriction fragment length polymorphism.

Blood sampling was done as follows: 6 ml of venous blood sample was collected from every participant and divided into three tubes: 2 ml of venous blood was put in EDTA-containing tube for CBC, peripheral blood film, and immunophenotyping, 2 ml of venous blood were put in EDTA-containing a tube for DNA analysis, and 2 ml were put in plain tube where sera were used for measurement of LDH and β2 microglobulin.

DNA analysis was done as follows: genomic DNA was extracted from EDTA anticoagulated peripheral blood (QIAamp DNA Blood Mini Kit; Qiagen GmbH, Hilden, Germany). Genotyping of VEGF + 936C/T single nucleotide polymorphism was carried out by PCR-restriction fragment length polymorphism method. A fragment containing the polymorphic site was amplified using the following primers: 5'-AAGGAAGAGGAGA TCTGCGAGAGC-3' (forward) and 5'-TAAATGTATGTATGTGGG TGGGTGTGTCTAAGG-3' (reverse). In a total volume of 50 μl, the reaction mixture contained 25 μl MyTaq HS Red Mix, 2x Kit (Bioline, Bioline meridian life science USA, Inc. 5171 Wilfong Rd. Memphis TN 38134), 1 μl of each primer, 5 μl of genomic DNA, and 18 μl of DNase-free and RNase-free water. PCR conditions consisted of initial denaturation at 95°C for 1 min, followed by 35 cycles of 95°C for 15 s, 64°C for 15 s, and 72°C for 10 s, and a terminal elongation step at 72°C for 5 min. PCR amplification was performed on a preprogrammed thermal cycler (Gene Amp PCR System 2400 Thermal Cycler; PerkinElmer, Waltham, Massachusetts, USA) [Figure 1]. Ten microliters of the PCR product (208 bp) was restricted by 1 μl Fast Digest NlaIII enzyme (NlaIII, #R0125S; New England Biolabs, Ipswich, Massachusetts, USA) at 37°C for 15 min with 208 bp fragment corresponded to C allele (restriction site absent) and a set of 122 and 86 bp fragments corresponded to T allele (restriction site present) after separation in 3% agarose gel containing ethidium bromide, as shown in [Figure 2].
Figure 1: VEGF + 936C/T gene after amplification. Lane 1: 50-bp DNA ladder and lane 2–13 bands correspond to ladder band size of 208 bp.

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Figure 2: Agarose gel electrophoresis of VEGF + 936C/T gene polymorphism after digestion by NlaIII restriction enzyme. Lane 1 shows DNA ladder (50 bp); lanes 2, 6, and 8 represent CC homozygote genotype (single 208 bp band); lane 3 represents variant TT homozygote genotype (two bands: 122 and 86 bp); and lanes 4, 5, 7, and 9 represent CT heterozygote genotype (three bands: 208, 122, and 86 bp).

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Statistical analysis

The statistical package for the social sciences software (version 20.0; SPSS Inc., Chicago, Illinois, USA) on an IBM personal computer was used for analyses. The χ2-test and the Fisher exact test were used when comparing qualitative data. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the risk conferred by a particular allele and genotype. The Student t-test was used to test the difference between normally distributed quantitative data among the studied groups. The Mann–Whitney U-test was used to test the difference between not normally distributed quantitative data among the studied groups. All tests were two tailed, and statistical significance was assumed at a P value less than 0.05.


  Results Top


In this study, distribution of VEGF + 936C/T polymorphism in Egyptian population was 66.7% CC genotype, 26.7% CT genotype, and 6.7% TT genotype in patients with CLL, whereas 75% CC, 25% CT, and 0.0% TT genotypes in the healthy control population. The CC genotype was higher in control compared with patients, whereas the CT and TT genotypes were higher in patients than the control group (no statistical difference, with P = 0.664).

Regarding allele frequency, the C allele was higher in control (87.5%) compared with patients (80%). However, T allele was higher in patients (20%) than in controls (12.5%) (no statistical difference, with P = 0.328).

OR showed that heterozygous genotype CT is more risky than homozygous genotype CC 'reference group' by 1.200 (95% CI: 0.326–4.415). However, the TT genotype has no OR, as the TT genotype in controls was zero. The dominant genetic model (CC vs. CT + TT) is also risky, as OR was 1.500 (95% CI = 0.423–5.316). The T allele is more risky than the C allele by 1.750 (95% CI = 0.565–5.421) [Table 1].
Table 1: Genotype frequencies and allelic distribution of VEGF+ 936C/T gene polymorphism among patients with chronic lymphocytic leukemia and control participants

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Concerning the relation between genotype distribution and sex, age, and somatic hypermutation in patients with CLL, there was no statistically significant relationship.

Regarding the different parameters of CBC, there was no statistically significant relationship between genotype distribution and hemoglobin, total leukocytic count, and absolute lymph, whereas the relation between TT genotype and recessive genetic model (CT + CC) with the platelet revealed a statistically significant relationship (P = 0.014) [Table 2].
Table 2: Mean hemoglobin, total leukocytic count, platelets, and absolute lymphocytes in relation with VEGF+ 936C/T genotypes in the case group (n=30)

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We also found that there was a statistically significant relationship between both TT genotype and recessive genetic model (CT + CC) and LDH and β2 microglobulin (P < 0.001 and 0.040, respectively) [Table 3].
Table 3: Relation between VEGF +936C/T genotypes with lactate dehydrogenase and β2 microglobulin in cases group (n=30)

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Regarding modified Rai staging system, there was a statistically significant relationship between TT genotype and recessive genetic model (CT + CC) with stage IV in patients with CLL (P = 0.028) [Table 4].
Table 4: Relation between VEGF +936C/T genotypes and modified Rai staging system in the case group (n=30)

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  Discussion Top


CLL is a monoclonal disorder characterized by a progressive accumulation of CD5-positive and CD19-positive small lymphocytes [4].

Several studies employed a variety of markers for diagnosing patients with CLL. It has been shown that various cellular and molecular biomarkers including chromosomes abnormalities, protein expression levels, types of mutations, epigenetic modifications, and miRNAs are associated with the prognosis in patients with CLL [10].

Dysregulation of angiogenesis plays an important role in the pathophysiology of CLL, probably through abnormal neovascularization of the bone marrow microenvironment [11].

VEGF is a dimeric glycoprotein, a potent cell mitogen that stimulates endothelial cell proliferation and migration, enhances vascular permeability, reduces endothelial cell apoptosis, promotes stromal proteolysis, and leads to angiogenic growth of new blood vessels [12]. It binds to tyrosine kinase transmembrane receptor (VEGF receptor) on the endothelial cell surface. VEGF/VEGF receptor interaction starts intracellular signal transduction pathways that mediate angiogenesis and vascular permeability [13].

Rogers and D'Amato [5] suggested that association between a disease and VEGF polymorphisms does not necessarily mean that the disease is angiogenesis dependent, for example, Debrah et al. [14] and Huang et al. [15] evaluated the role of VEGF genetic polymorphisms in acute macular degeneration and in hydrocele development in a cohort of patients with lymphatic filariasis, respectively. However, because these conditions are characterized by extensive vascular leak, it is likely that the effect is mediated by induction of vascular permeability by VEGF, rather than by angiogenesis.

In this study, we aimed to evaluate the association of VEGF + 936C/T gene polymorphism in Egyptian patients with B-CLL. It included 30 adult patients diagnosed with CLL and 20 age-matched and sex-matched healthy controls. Diagnosis of CLL was based on morphology and immunophenotyping.

VEGF + 936C/T gene polymorphism showed no significant differences in the distribution of the genotypes and allele frequencies between patients and controls (P = 0.664 and 0.328, respectively).

This agrees with Bakirov et al. [16]. In addition, Wróbel et al. [17] reported that slight prevalence of VEGF variant was detected among patients with CLL as compared with healthy control (P = 0.095; OR = 1.91). Moreover, Lakkireddy et al. [18] reported that no significant association between the gene polymorphism and development of other types of leukemic diseases such as chronic myeloid leukemia.

Our results are in harmony with many studies which proved that the result of + 936C/T polymorphism exhibited a nonsignificant association with urothelial bladder cancer, by Ben Wafi et al. [19], lung cancer by Naikoo et al. [20], breast cancer by Kapahi et al. [21] and pancreatic adenocarcinoma by Sivaprasad et al. [22].

Our data are matched with Cao et al. [23]. They conducted a meta-analysis to study the association between the VEGF + 936C/T polymorphism and cancer risk by reviewing 29 studies and found no association between the VEGF + 936C/T polymorphism and the risk of cancer, including colorectal cancer, gastric cancer, breast cancer, ovarian cancer, mantle cell lymphoma, and lung cancer. However, the meta-analysis on two available studies only showed that the 936T allele was associated with a significant increase in oral cancer risk.

Concerning clinical correlation, we found no relationship between hepatosplenomegaly and VEGF + 936C/T genotypes, which is in contrast to Lakkireddy et al. [18] who found that VEGF CT genotype had a positive association with splenomegaly in patients with chronic myeloid leukemia.

Furthermore, we found out that both VEGF + 936 TT genotype and recessive genetic model (CT + CC) had a positive significant relation with the poor prognostic markers LDH and β2 microglobulin. Our results agree with Wróbel et al. [17] regarding β2 microglobulin, whereas Lakkireddy et al. [18] demonstrated a negative association of CT genotype with LDH levels.

Véronèse et al. [24] explained that a high level of VEGF may contribute to an increased level of Mcl-1 protein expression and greater apoptosis resistance of CLL cells. In addition, it is associated with downregulation of metalloproteinase-9, which results in the inhibition of CLL cell migration, and also regulates the microenvironment-cancer cell interactions, as stated by Ugarte-Berzal et al. [25].

Regarding Rai staging, this study shows a significant relationship between both TT genotype and recessive genetic model (CT + CC) and stage IV in patients with CLL (P = 0.028). Similarly, Wróbel et al. [17] observed an increased frequency of the + 936C/T mutant T allele in patients with advanced stages (Rai III/IV), and they suggested that VEGF-based autocrine pathway promotes the survival of B-CLL cells through up-regulation of anti-apoptotic proteins. Moreover, Rozovski et al. [26] added that STAT proteins, mainly STAT3, have been ascribed oncogenic potential, as it was shown to be associated with tumor initiation and progression owing to the facilitation of cellular expansion by trans-activating genes encoding pro-survival factors, such as Bclxl or Bcl2.

In a study done by Wróbel et al. [27] in patients with non-Hodgkin's lymphoma, they depicted that VEGF + 936 T allele was significantly associated with a worse prognosis expressed by the highest International Prognostic Index (3 and/or 4) In addition, Bakry et al. [28] revealed that the VEGF + 936 T allele showed a trend of significance toward a worse prognosis and advanced staging in non-Hodgkin's lymphoma.

Interestingly, Corvalan et al. [29] stated that several polymorphisms on the VEGF gene were thought to affect its expression. Certain allele variation may lead to overexpression of the transcription factor that will bind to the promoter site, which serves as the initial RNA polymerase binding site that will initiate transcription.

Furthermore, Del Bo et al. [30] elucidated that polymorphisms in angiogenesis-regulating genes can affect a large number of phenotypes, including a wide variety related to disease processes in human. The absence of association does not imply that the gene/protein in question is not involved in disease. Rather, it may simply mean that the functional polymorphisms in the gene have not been identified or do not exist at sufficient frequency in the study populations.

In conclusion, our work revealed that despite VEGF + 936C/T gene polymorphism showing no significant differences in the distribution of the genotypes and allele frequencies between patients and controls, CT and TT (mutant) genotypes were higher in patients than the controls. We also depicted that the VEGF + 936C/T gene polymorphism was significantly related to poor criteria of prognosis such as LDH, β2 microglobulin, and Modified Rai staging (stage IV).

Finally, further prospective and multiethnic studies, including large sample size, are required to confirm our finding with particular attention to the role of gene–gene and gene–environment interaction. We also recommend measurement of serum VEGF to analyze the relationship between the polymorphism and expression of the gene; this constitutes a limitation of our study.


  Conclusion Top


VEGF + 936C/T gene polymorphism can predict poor prognosis in patients with CLL.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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