- Research
- Open access
- Published:
Association of VEGFR1, VEGFR2 and VEGFR3 polymorphisms with esophageal cancer risk: a case–control study
Egyptian Journal of Medical Human Genetics volume 25, Article number: 93 (2024)
Abstract
Background
Esophageal cancer is the eleventh most common cancer and is the seventh leading cause of mortality worldwide. Vascular endothelial growth factor (VEGF) and its receptors pathway are a key regulator of angiogenesis and play an important role in carcinogenesis. The aim of current study was to evaluate the association of five VEGFR polymorphisms with esophageal cancer risk in patients from Punjab, North-west India.
Methods
This case–control study included 310 esophageal cancer patients and 325 age and gender matched healthy controls. VEGFR1-710C/T, VEGFR2-604 T/C (rs2071559), VEGFR2 1192 G/A (rs2305948), VEGFR2 1719A/T (rs1870377) and VEGFR3 (rs72816988) polymorphisms were genotyped by using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. Restriction digestion products were analyzed on 2.4% agarose gel and genotype was assigned to each sample on the basis of fragments obtained after digestion. Randomly 10% samples were repeated by Sanger sequencing to revalidate the results.
Results
There was a significant association of CT genotype (OR = 0.28; 95%CI, 0.10–0.76; p = 0.01) and T allele (OR = 0.28; 95%CI, 0.10–0.77; p = 0.01) of VEGFR1-710C/T polymorphism with decreased risk of esophageal cancer. TC genotype of VEGFR2-604 T/C (OR = 0.66; 95%CI, 0.44–0.97; p = 0.03) and GA genotype of VEGFR2 1192G/A (OR = 0.54; 95%CI, 0.31–0.95; p = 0.03) polymorphisms were significantly associated with decreased risk of esophageal cancer. There was no significant difference in allele and genotype frequency of VEGFR2 1719A/T and VEGFR3 (rs72816988) polymorphisms between esophageal cancer patients and controls (p > 0.05). Haplotype analysis revealed that haplotype C-604A1719A1192 was significantly associated with the decreased esophageal cancer risk (OR = 0.44; 95%CI, 0.23–0.84; p = 0.01).
Conclusion
VEGFR1-710C/T, VEGFR2-604 T/C and VEGFR2 1192G/A polymorphisms were associated with the decreased risk of esophageal cancer in patients from Punjab, North-west India.
Graphical abstract
![](http://media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs43042-024-00564-9/MediaObjects/43042_2024_564_Figa_HTML.png)
Background
The growth of solid tumors including esophageal cancer depends on angiogenesis for the supply of oxygen and nutrients for their continuous growth. Angiogenesis is regulated by cellular signaling mediated by vascular endothelial growth factor (VEGF) and its receptors [1, 2]. VEGF triggers its signaling via VEGFR1, VEGFR2 and VEGFR3 receptors, which are the members of receptor tyrosine kinase family. It has been reported that VEGFR1 or FLT had greater affinity for VEGF as compared to VEGFR2, but had lower tyrosine kinase activity [3,4,5]. VEGFR1 is one of the important receptors of VEGF angiogenesis signaling pathway and its expression is upregulated by hypoxia via HIF-1-dependent mechanism [6, 7]. VEGFR2 or KDR had higher affinity for VEGF-A and VEGF-E and lower affinity for VEGF-C and VEGF-D [8, 9]. von Willebrand factor is secreted by endothelial cells when VEGF binds with VEGFR2 and was reported to be one of the negative prognostic factors for many solid tumors [3, 10]. It has been documented that VEGF-VEGFR2 signaling cascade facilitates tumor growth, invasion and therapeutic resistance [11]. VEGFR1 and VEGFR2 have been described as major therapeutic targets for sorafenib [2]. VEGFR3 or FLT-4 has an affinity for VEGF-C and VEGF-D and its expression influenced the differentiation of lymphatic endothelial cells, tubulogenesis, proliferation, migration and survival of lymphatic endothelial cells [3, 8].
Biomarkers like single-nucleotide polymorphisms (SNPs) account for much of the genetic variations including disease susceptibility, prognosis and response to therapy. The angiogenic pathway, and hence the susceptibility and severity of cancer, may be affected by polymorphisms alone or in combination with environmental factors [12]. It has been reported that SNPs in VEGFRs may affect the production and functioning of protein, thus resulting in dysregulation of angiogenic pathway [13]. Several SNPs have been identified in the VEGFR2, some of which have the ability to alter gene expression, amount of circulating VEGFR2 levels and the efficiency with which VEGF binds to the receptor [14]. Genetic location of the VEGFR1, VEGFR2 and VEGFR3 polymorphisms is given in Fig. 1.
Association of VEGFR1, VEGFR2 and VEGFR3 polymorphisms with risk of some of gastrointestinal tract (GIT) cancers has been reported in different populations. The G allele of VEGFR2-604A/G polymorphism was associated with increased risk of pancreatic cancer in Romanian population [15]. Combined TT + TC genotype of VEGFR2-604 T/C polymorphism was associated with improved overall survival in Danish colorectal cancer patients [16]. The CC genotype of VEGFR2 1192 T/C polymorphism was associated with improved survival in Danish colorectal cancer patients [16]. In Han Chinese population, TC genotype of VEGFR2 1192 T/C polymorphism was associated with low overall survival in hepatocellular cancer patients [17]. The T allele of VEGFR2 1416A/T polymorphism was found to be associated with increased risk of hepatocellular carcinoma in Portuguese population [18]. In Chinese gastric cancer patients, AA genotype of VEGFR2 1719 A/T polymorphism was associated with poor prognosis [19]. So far, there is no published study that has investigated the role of VEGFR1-710C/T and VEGFR3 rs72816988 polymorphisms in any of the GIT cancers.
Esophageal cancer is the eleventh most common cancer and is the seventh leading cause of mortality worldwide [20]. The highest regional standardized incidence and mortality of esophageal cancer was found in Eastern Asia, followed by Eastern Africa, Southern Africa and South-Central Asia [21]. According to Globocan 2020, nearly 79.7% of new esophageal cancer cases were found in Asia [22]. China had the largest number of new esophageal cancer cases, accounting for 67.3% of in Asia and 53.70% of cases worldwide, and India has the second highest number of new esophageal cancer cases in both Asia and the world, with 63,180 new cases [22]. In Punjab, esophageal cancer is the fourth leading cause of death in women and the second leading cause of mortality in men [23]. Histologically, esophageal cancer has two main subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), and they both differ in their incidence and risk factors profiling. Potential risk factors that one may have for being diagnosed with EAC are obesity, gastroesophageal reflux disease (GERD), male sex, white race and cigarette smoking (or a history of smoking) [24]. For ESCC, the potential risk factors are black race, smoking, alcohol drinking, diet rich in tea, coffee, tobacco chewing, and “chewers of areca nut” which is commonly consumed in regions such as Southeast Asia and India [25].
VEGF/VEGFR pathway is the key regulator of angiogenesis and plays an important role in carcinogenesis [26]. From the early phases of carcinogenesis to the final stage of the disease, angiogenesis plays a significant role in esophageal cancer, and angiogenesis-related agents are being investigated as potential targets for new treatments for esophageal cancer [27]. Therefore, the present study aimed to evaluate the association of VEGFR1-710C/T, VEGFR2-604 T/C (rs2071559), VEGFR2 1192 G/A (rs2305948), VEGFR2 1719A/T (rs1870377) and VEGFR3 (rs72816988) polymorphisms with esophageal cancer risk in patients from Punjab, North-west India. Identification of association of SNPs can aid in predicting the clinical response to the various therapeutic drugs used in the treatment of esophageal cancer. To best of our knowledge, this is the first study evaluating the association of five VEGFR polymorphisms with esophageal cancer risk.
Material and methods
Study subjects
The present case–control study was carried out in accordance with the guidelines of the Helsinki Declaration and was approved by the ethics committee of Guru Nanak Dev University, Amritsar, Punjab, India. In this case–control study design, 310 esophageal cancer patients (137 males and 173 females) and 325 (144 males and 181 females) age and gender matched healthy controls from same ethnicity were investigated based on the predefined inclusion and exclusion criteria (Table 1). The sample size was calculated by using online software Cats Power Calculator (https://csg.sph.umich.edu/abecasis/cats/gas_power_calculator/index.html) using data of minor allele frequency of VEGFR1, VEGFR2 and VEGFR3 polymorphisms from dbSNP (1000 Genome Data). The threshold for significance was set at 0.05, and relative risk was set at 1.5. Five milliliter intravenous blood sample of each subject was collected in EDTA vials after obtaining the written informed consent from all the subjects. The patients were investigated at Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India. The blood samples were transported to the Department of Human Genetics, Guru Nanak Dev University, Amritsar, in an ice box from the site of sample collection. Unique code was given to each sample and was stored at − 20℃ till further processing. Demographic characteristics of study participants are shown in Table 2.
Genomic DNA extraction and genotyping of VEGFR polymorphisms
Genomic DNA was extracted from blood samples using standard phenol chloroform method with few modifications [28]. The procedure of DNA extraction is given in Supplementary file 1. Quantity and quality of DNA samples was analyzed on 1% agarose gel. VEGFR1-710C/T, VEGFR2-604 T/C (rs2071559), VEGFR2 1192 G/A (rs2305948), VEGFR2 1719A/T or 1416A/T (rs1870377) and VEGFR3 (rs72816988) polymorphisms were screened by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method (Figs. 2, 3, 4, 5, 6).
The targeted regions of VEGFR1, VEGFR2 and VEGFR3 were amplified using published primer sequence [29,30,31]. The reaction volume used for amplification was 15 µl, and it contained 75 ng of template DNA, 1.5 µl of 10X Taq Buffer A with 15 mM MgCl2, 6 pmol of each primer, 0.3 µl of dNTPs mixture and 1 U Taq DNA polymerase. Amplified PCR products were analyzed on 2% agarose gel. PCR products were further digested with specific restriction enzymes as per manufacturer’s instructions. For VEGFR1-710C/T polymorphism, NlaIII restriction enzyme (New England BioLabs) was used to digest the 665-bp PCR products. For VEGFR2-604 T/C polymorphism, BsmI restriction enzyme (New England BioLabs) was used to digest the 290-bp PCR products. For VEGFR2 1192G/A polymorphism, BstZ17I-HF restriction enzyme (New England BioLabs) was used to digest the 262-bp PCR products. For VEGFR2 1719A/T polymorphism, AluI restriction enzyme (New England BioLabs) was used to digest the 404-bp PCR products. For VEGFR3 (rs72816988) polymorphism, the amplified products of 218 bp were digested with AciI restriction enzyme (New England BioLabs). The digestion was done for overnight at 37 °C for VEGFR1-710C/T, VEGFR2 1192G/A, VEGFR2 1719A/T and VEGFR3 (rs72816988) polymorphisms, whereas for VEGFR2-604 T/C polymorphism digestion was done at 65 °C. Restriction digestion products were analyzed on 2.4% agarose gel. Genotype was assigned to each sample on the basis of fragments obtained after digestion. The amplification and genotype conditions are given in Table 3. Randomly 10% samples were repeated by Sanger sequencing to revalidate the results and 100% concordance was found (Figs. 2, 3, 4, 5, 6).
Statistical analysis
The Hardy–Weinberg equilibrium (HWE) was evaluated to compare the observed and expected genotype frequencies among controls using Chi-square test. The differences in the genotype and allele frequencies of VEGFR1, VEGFR2 and VEGFR3 polymorphisms between the patients and controls were compared. Odds ratio (OR) and 95% confidence intervals were calculated by MedCalc software [32] to find the association of alleles and genotypes with esophageal cancer risk. SNPstats online software was used to study the different genetic models and haplotypes [33]. p-value less than 0.05 was considered as statistically significant for all the statistical analysis.
Results
A total of 310 esophageal cancer patients and 325 healthy controls were analyzed in this study. The genotype distribution for the studied VEGFR2 polymorphisms was in Hardy–Weinberg equilibrium in controls.
Association of VEGFR1-710C/T polymorphism
The frequency of the CC and CT genotype of VEGFR1-710C/T polymorphism was 98.39 vs 94.46% and 1.61 vs 5.54% in patients and controls, respectively (Table 4). TT genotype was not observed in any of the subjects. CT genotype (OR = 0.28; 95%CI, 0.10–0.76; p = 0.01) and T allele (OR = 0.28; 95%CI, 0.10–0.77; p = 0.01) was found to be significantly associated with decreased risk of esophageal cancer.
Association of VEGFR2 polymorphisms
The frequency of TC genotype of VEGFR2-604 T/C polymorphism was higher in controls (Table 4) and was associated with decreased risk of esophageal cancer (OR = 0.66; 95%CI, 0.44–0.97; p = 0.03). After stratification of the data according to gender, TC genotype of VEGFR2-604 T/C was found to be significantly associated with decreased risk of esophageal cancer in male group (OR = 0.50; 95%CI, 0.28–0.89; p = 0.02) (Table 5). Genetic model analysis of VEGFR2-604 T/C polymorphism showed a decreased risk of esophageal cancer under codominant (OR = 0.66; 95%CI, 0.44–0.97; p = 0.03) and dominant model (OR = 0.66; 95%CI, 0.46–0.96; p = 0.03) (Table 6). In male group, decreased esophageal cancer risk was observed under codominant (OR = 0.50; 95%CI, 0.28–0.89; p = 0.02) and dominant model (OR = 0.53; 95%CI, 0.31–0.92; p = 0.02) (Table 7).
In female group, GA genotype of VEGFR2 1192G/A polymorphism was found to be significantly associated with decreased esophageal cancer risk (OR = 0.54; 95%CI, 0.31–0.95; p = 0.03). Genetic model analysis of VEGFR2 1192G/A polymorphism revealed a significantly decreased esophageal cancer risk in codominant (OR = 0.54; 95%CI, 0.31–0.95; p = 0.03), dominant (OR = 0.56; 95%CI, 0.32–0.96; p = 0.04), and overdominant model (OR = 0.54; 95%CI, 0.31–0.95; p = 0.03) in female group. We further compare the genotype distribution of VEGFR2 1192G/A polymorphism between male patients and female patients and observed that GA genotype was significantly associated with increased risk of esophageal cancer in male patients as compared to female patients (Table 8). There was no significant difference in the genotype and allele frequencies of VEGFR2 1719A/T polymorphism between patients and controls (Table 4).
Association of VEGFR3 (rs72816988) polymorphism
The frequency of the GG and GA genotype of VEGFR3 (rs72816988) polymorphism was 95.16 vs 94.46% and 4.84 vs 5.54% in patients and controls, respectively. AA genotype was not observed in any of the subjects. There was no significant difference in genotype and allele frequencies between patients and controls (Table 4).
Haplotype analysis
To evaluate the combined effect of VEGFR2 polymorphisms in the susceptibility to esophageal cancer, haplotype analysis was performed. In total subjects, haplotype C-604 A1719A1192 was significantly associated with the decreased esophageal cancer risk (OR = 0.44; 95%CI, 0.23–0.84; p = 0.01), whereas haplotype C-604 A1719G1192 was marginally associated with the decreased cancer risk (OR = 0.74; 95%CI, 0.54–1.01; p = 0.06). Haplotype C-604 A1719G1192 was significantly associated with the decreased esophageal cancer risk in male group (OR = 0.48; 95%CI, 0.28–0.80; p = 0.006) (Table 9).
Discussion
In the present study, we have investigated the association of VEGFR1-710C/T, VEGFR2-604 T/C, VEGFR2 1192 G/A, VEGFR2 1719A/T and VEGFR3 (rs72816988) polymorphisms with esophageal cancer risk. Researchers have investigated these polymorphisms in different cancers and results are variable (Supplementary Tables 1–4). So far, the role of these polymorphisms has not been explored in esophageal cancer. In the present study, T allele of VEGFR1-710C/T polymorphism was significantly associated with decreased risk of esophageal cancer. Till date, there is no published study on VEGFR1-710C/T polymorphism in gastrointestinal tract cancer. Association of T allele with reduced breast cancer risk has been reported in Spanish population [29], whereas no association of VEGFR1-710C/T polymorphism with breast cancer risk has been reported in patients from Punjab North-west India [34].
The promoter polymorphism VEGFR2-604 T/C changes the binding site for transcription factor E2F in KDR promoter region, which can downregulate KDR expression [14]. In the present study, TC genotype of VEGFR2-604 T/C polymorphism was significantly associated with reduced risk of esophageal cancer. The TC + CC combined genotype of VEGFR2-604 T/C polymorphism was associated with decreased esophageal cancer risk in dominant model. Contrary to our results, combined TC + CC genotype was significantly associated with increased risk of colorectal cancer in Korean population [35]. The C allele of VEGFR2-604 T/C polymorphism was associated with increased risk of pancreatic cancer in Romanian population [15]. However, no correlation of VEGFR2-604 T/C polymorphism has been observed with gastric cancer [19] and hepatocellular carcinoma in Chinese population [17]. In Danish population, TT + TC genotype of VEGFR2-604 T/C was associated with improved overall survival in colorectal cancer patients [16].
VEGFR2 1192G/A polymorphism located in third NH2 terminal Ig-like domains in the extracellular region is crucial for ligand binding [14]. In the present study, no association was found between VEGFR2 1192G/A polymorphism and esophageal cancer in total subjects. However, combined GA + AA genotype was significantly associated with decreased esophageal cancer risk in female group. Association of combined GA + AA genotype of VEGFR2 1192G/A polymorphism with increased colorectal cancer risk has been documented in Korean population [35]. In Danish population, GG genotype of VEGFR2 1192G/A polymorphism was associated with improved survival in patients having colorectal cancer [16]. GA genotype was associated with lower overall survival in hepatocellular cancer Han Chinese patients [17]. No correlation was observed between VEGFR2 1192G/A polymorphism and gastric cancer in Chinese population [19].
In the present study, VEGFR2 1719A/T polymorphism was not associated with esophageal cancer risk. VEGFR2 1719A/T polymorphism was not associated with recurrence and overall survival in esophageal adenocarcinoma patients who underwent surgery [36]. Similarly, no association of VEGFR2 1719A/T polymorphism has been reported in hepatocellular carcinoma in Han Chinese [17] and colorectal cancer in Danish patients [16]. The T allele of VEGFR2 1719A/T polymorphism was associated with increased hepatocellular cancer risk in Portuguese patients [18], whereas AA genotype was associated with poor prognosis in Chinese gastric cancer patients [19].
No significant association was observed between VEGFR3 (rs72816988) polymorphism and esophageal cancer risk in the present study. Till date, there is no published study on VEGFR3 (rs72816988) polymorphism in GIT cancer. Relationship between VEGFR3 (rs72816988) polymorphism with the clinical outcomes of renal cell carcinoma patients treated with sorafenib [37] and sunitinib [31] has been studied, and no association was found in both of these studies.
In the present study, C-604 A1719A1192 haplotype of VEGFR2 was significantly associated with decreased esophageal cancer risk in total subjects, whereas C-604 A1719G1192 haplotype was associated with decreased esophageal cancer risk in male group. Association of C-604G1192 and C-604A1192 haplotypes with an increased risk to colorectal cancer has been reported in Korean patients [35]. The response of VEGFR polymorphisms with different therapies in GIT cancers has been studied in different populations and reported association with disease survival (Supplementary Tables 5–7).
Strength of the study
So far, the present case–control study is the first study which have analyzed the association of VEGFR1-710C/T, VEGFR2-604 T/C, VEGFR2 1192 G/A, VEGFR2 1719A/T and VEGFR3 (rs72816988) polymorphisms with esophageal cancer risk. It provides the baseline data for genetic polymorphisms of angiogenic pathway.
Limitations of the study
The present study only focuses on the population of Punjab, North-west India, with a limited sample size; however, the frequency of genetic polymorphisms often varies between different ethnic groups.
Conclusion and future directions
In the present study, we found that VEGFR1-710C/T, VEGFR2-604 T/C and VEGFR2 1192G/A polymorphisms were associated with decreased risk of esophageal cancer in the patients from Punjab, North-west India. In future, further studies with larger sample size on different ethnic groups are required to better understand the role of VEGFR polymorphisms in the development and progression of esophageal cancer. Understanding the relationship between VEGFR polymorphisms and esophageal cancer risk can aid in identifying individuals at higher risk and facilitate early detection and intervention which is crucial for better prognosis. In future, studies examining the relationship between VEGFR polymorphisms and the response of esophageal cancer patients to chemotherapeutic drugs are required. This will help to understand how these polymorphisms affect treatment response and aid in the provision of personalized medicine, which aims to maximize therapeutic outcomes and minimizing adverse effects.
Availability of data and materials
All the data relevant to this study has been included in the manuscript or uploaded as supplementary files.
Abbreviations
- VEGF:
-
Vascular endothelial growth factor
- VEGFR:
-
Vascular endothelial growth factor receptor
- GIT:
-
Gastrointestinal tract
- SNP:
-
Single-nucleotide polymorphism
- PCR–RFLP:
-
Polymerase chain reaction–restriction fragment length polymorphism
- EDTA:
-
Ethylenediaminetetraacetic acid
- HWE:
-
Hardy–Weinberg equilibrium
- OR:
-
Odds ratio
- CI:
-
Confidence interval
References
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676
Peng S, Wang Y, Peng H, Chen D, Shen S, Peng B et al (2014) Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma. Hepatology 60:1264–1277
Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom T, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580
Cébe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A et al (2006) A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci 63:2067–2077
Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2:a006502
Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes: Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667
Menendez D, Krysiak O, Inga A, Krysiak B, Resnick MA, Schönfelder G (2006) A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network. Proc Natl Acad Sci U S A 103:1406–1411
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol 7:359–371
Niu G, Chen X (2010) Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr Drug Targets 11:1000–1017
Zanetta L, Marcus SG, Vasile J, Dobryansky M, Cohen H, Eng K et al (2002) Expression of Von Willebrand factor, an endothelial cell marker, is up-regulated by angiogenesis factors: a potential method for objective assessment of tumor angiogenesis. Int J Cancer 85:281–288
Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560
Balasubramanian SP, Brown NJ, Reed MW (2002) Role of genetic polymorphisms in tumour angiogenesis. Br J Cancer 87:1057–1065
Ravegnini G, Nannini M, Zenesini C, Simeon V, Sammarini G, Urbini M et al (2017) An exploratory association of polymorphisms in angiogenesis-related genes with susceptibility, clinical response and toxicity in gastrointestinal stromal tumours receiving sunitinib after imatinib failure. Angiogenesis 20:139–148
Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y et al (2007) Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol 50:760–767
Pădureanu V, Boldeanu MV, Streaţă I et al (2017) Determination of VEGFR-2 (KDR) 604A>G polymorphism in pancreatic disorders. Int J Mol Sci 18:439–448
Hansen TF, Sørensen FB, Spindler KL, Olsen DA, Andersen RF, Lindebjerg J et al (2010) Microvessel density and the association with single nucleotide polymorphisms of the vascular endothelial growth factor receptor 2 in patients with colorectal cancer. Virchows Arch 456:251–260
Wang W, Ma XP, Shi Z, Zhang P, Ding DL, Huang HX et al (2014) Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma. Am J Cancer Res 5:396–410
Machado MV, Janeiro A, Miltenberger-Miltenyi G, Cortez-Pinto H (2014) Genetic polymorphisms of proangiogenic factors seem to favor hepatocellular carcinoma development in alcoholic cirrhosis. Eur J Gastroenterol Hepatol 26:438–443
Zhu X, Wang Y, Xue W, Wang R, Wang L, Zhu ML et al (2019) The VEGFR-2 protein and the VEGFR-2 rs1870377 A>T genetic polymorphism are prognostic factors for gastric cancer. Cancer Biol Ther 20:497–504
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74:229–263
Liu CQ, Ma YL, Qin Q, Wang PH, Luo Y, Xu PF et al (2023) Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer 14:3–11
Zhu H, Wang Z, Deng B, Mo M, Wang H, Chen K et al (2023) Epidemiological landscape of esophageal cancer in Asia: results from GLOBOCAN 2020. Thorac Cancer 14(11):992–1003
India State-Level Disease Burden Initiative Cancer Collaborators (2018) The burden of cancers and their variations across the states of India: the global burden of disease study 1990–2016. Lancet Oncol 19:1289–1306
Huang FL, Yu SJ (2018) Esophageal cancer: risk factors, genetic association, and treatment. Asian J Surg 41:210–215
Domper Arnal MJ, Ferrández Arenas Á, Lanas Arbeloa Á (2015) Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol 21:7933–7943
Rapisarda A, Melillo G (2012) Role of the VEGF/VEGFR axis in cancer biology and therapy. Adv Cancer Res 114:237–267
Kumagai Y, Toi M, Kawada K, Kawano T (2010) Angiogenesis in superficial esophageal squamous cell carcinoma: magnifying endoscopic observation and molecular analysis. Dig Endosc 22:259–267
Adeli K, Ogbonna G (1990) Rapid purification of human DNA from whole blood for potential application in clinical chemistry laboratories. Clin Chem 36:261–264
Rodrigues P, Furriol J, Tormo E, Ballester S, Lluch A, Eroles P (2012) The single-nucleotide polymorphisms +936 C/T VEGF and -710 C/T VEGFR1 are associated with breast cancer protection in a Spanish population. Breast Cancer Res Treat 133:769–778
Nouri K, Haslinger P, Szabo L, Sator M, Schreiber M, Schneeberger C et al (2014) Polymorphisms of VEGF and VEGF receptors are associated with the occurrence of ovarian hyperstimulation syndrome (OHSS)-a retrospective case-control study. J Ovarian Res 7:54–61
Liu R, Wang X, Li W, Shou T, Zhou L, Li Y et al (2017) Influence of VEGFR single nucleotide polymorphisms on the efficacy of sunitinib therapy against renal cell carcinoma. Oncol Lett 13:201–205
Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929
Kapahi R, Guleria K, Sambyal V, Manjari M, Sudan M, Uppal MS et al (2015) Association of VEGF and VEGFR1 polymorphisms with breast cancer risk in North Indians. Tumour Biol 36:4223–4234
Jang MJ, Jeon YJ, Kim JW, Cho YK, Lee SK, Hwang SG et al (2013) Association of VEGF and KDR single nucleotide polymorphisms with colorectal cancer susceptibility in Koreans. Mol Carcinog 52:60–69
Lurje G, Leers JM, Pohl A, Oezcelik A, Zhang W, Ayazi S et al (2010) Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus. Ann Surg 251:857–864
Qin C, Cao Q, Li P, Wang S, Wang J, Wang M et al (2016) The influence of genetic variants of sorafenib on clinical outcomes and toxic effects in patients with advanced renal cell carcinoma. Sci Rep 6:20089–20098
Shchayuk AN, Krupnova EV, Shapetska MN, Mikhalenka AP, Chebotareva NV, Kilchevsky AV (2018) Association of polymorphic variants of VEGF and KDR genes with development and metastasing of non-small cell lung cancer. J Cancer Ther 9:714–729
Fraga A, Ribeiro R, Coelho A, Vizcaíno JR, Coutinho H, Lopes JM et al (2017) Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer. BMC Urol 17:12–24
Brito AB, Lourenço GJ, Oliveira GB, De Souza CA, Vassallo J, Lima CS (2014) Associations of VEGF and VEGFR2 polymorphisms with increased risk and aggressiveness of multiple myeloma. Ann Hematol 93:1363–1369
Hu K, Xie X, Wang R, Wu F, Zhang Y (2017) Association of the rs2071559 (T/C) polymorphism with lymphatic metastasis in patients with nasopharyngeal carcinoma. Oncol Lett 14:7681–7686
Vasconcelos VCA, Lourenço GJ, Brito ABC, Vasconcelos VL, Maldaun MVC, Tedeschi H et al (2019) Associations of VEGFA and KDR single-nucleotide polymorphisms and increased risk and aggressiveness of high-grade gliomas. Tumour Biol 41:1010428319872092
Xu GZ, Liu Y, Zhang Y, Yu J, Diao B (2015) Correlation between VEGFR2 rs2071559 polymorphism and glioma risk among Chinese population. Int J Clin Exp Med 8:16724–16728
Gao Y, Ma P, He Y, Liu Y, Jiang Y (2016) Genetic variations of kinase inserts domain receptor (KDR) gene are associated with the risk of astrocytomas. Mol Neurobiol 53:2541–2549
Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A et al (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672–4678
Försti A, Jin Q, Altieri A, Johansson R, Wagner K, Enquist K et al (2007) Polymorphisms in the KDR and POSTN genes: association with breast cancer susceptibility and prognosis. Breast Cancer Res Treat 101:83–93
Zhang J, Yang J, Chen Y, Mao Q, Li S, Xiong W et al (2016) Genetic variants of VEGF (rs201963 and rs3025039) and KDR (rs7667298, rs2305948, and rs1870377) are associated with glioma risk in a Han Chinese population: a case-control study. Mol Neurobiol 53:2610–2618
Verboom MC, Kloth JSL, Swen JJ, van der Straaten T, Bovée JVMG, Sleijfer S et al (2017) Genetic polymorphisms in angiogenesis-related genes are associated with worse progression-free survival of patients with advanced gastrointestinal stromal tumours treated with imatinib. Eur J Cancer 86:226–232
Scartozzi M, Faloppi L, Svegliati Baroni G, Loretelli C, Piscaglia F, Lavarone M et al (2014) VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study. Int J Cancer 135:1247–1256
Zheng YB, Zhan MX, Zhao W, Liu B, Huang JW, He X et al (2014) (2014) The relationship of kinase insert domain receptor gene polymorphisms and clinical outcome in advanced hepatocellular carcinoma patients treated with sorafenib. Med Oncol 31:209–217
Zheng YB, Huang JW, Zhan MX, Zhao W, Liu B, He X et al (2014) Genetic variants in the KDR gene is associated with the prognosis of transarterial chemoembolization treated hepatocellular carcinoma. Tumour Biol 35:11473–11481
Uzunoglu FG, Kolbe J, Wikman H, Güngör C, Bohn BA, Nentwich MF et al (2013) VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma. Ann Oncol 24:1282–1290
Gerger A, El-Khoueiry A, Zhang W, Yang D, Singh H, Bohanes P et al (2011) Pharmacogenetic angiogenesis profiling for first-line bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res 17:5783–5792
Hansen TF, Christensen RD, Andersen RF, Garm Spindler KL, Johnsson A, Jakobsen A (2012) The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer: results from the Nordic ACT trial. Int J Colorectal Dis 27:715–720
Dong G, Guo X, Fu X, Wan S, Zhou F, Myers RE et al (2012) Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer. Cancer Sci 103:561–568
Paré-Brunet L, Sebio A, Salazar J, Berenguer-Llergo A, Río E, Barnadas A et al (2015) Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy. Pharmacogenom J 15:397–404
Giampieri R, Salvatore L, Del Prete M, Prochilo T, D’Anzeo M, Loretelli C et al (2016) Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients. Sci Rep 6:25195–25205
Xie H, Lafky JM, Morlan BW, Stella PJ, Dakhil SR, Gross GG et al (2020) Dual VEGF inhibition with sorafenib and bevacizumab as salvage therapy in metastatic colorectal cancer: results of the phase II North central cancer treatment group study N054C (Alliance). Ther Adv Med Oncol 12:1758835920910913
Bai M, Li ZG, Ba Y (2021) Influence of KDR genetic variation on the efficacy and safety of patients with chemotherapy refractory metastatic CRC who received apatinib treatment. Int J Gen Med 14:1041–1055
Solini A, Simeon V, Derosa L, Orlandi P, Rossi C, Fontana A et al (2015) Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favourable prognostic profile in prostate cancer patients. Oncotarget 6:28743–28754
Scartozzi M, Bianconi M, Faloppi L, Loretelli C, Bittoni A, Del Prete M et al (2013) VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib. Br J Cancer 108:1126–1132
George DJ, Martini JF, Staehler M, Motzer RJ, Magheli A, Donskov F et al (2019) Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory pharmacogenomic analysis. Clin Cancer Res 25:1165–1173
Pallaud C, Reck M, Juhasz E, Szima B, Yu CJ, Burdaeva O et al (2014) Clinical genotyping and efficacy outcomes: exploratory biomarker data from the phase II ABIGAIL study of first-line bevacizumab plus chemotherapy in non-squamous non-small-cell lung cancer. Lung Cancer 86:67–72
Sullivan I, Riera P, Andrés M, Altés A, Majem M, Blanco R et al (2019) Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients. Angiogenesis 22:433–440
Babyshkina N, Zavyalova M, Tarabanovskaya N, Dronova T, Krakhmal N, Slonimskaya E et al (2018) Predictive value of vascular endothelial growth factor receptor type 2 in triple-negative breast cancer patients treated with neoadjuvant chemotherapy. Mol Cell Biochem 444:197–206
Dronova TA, Babyshkina NN, Zavyalova MV, Slonimskaya EM, Cherdyntseva NV (2021) Vascular endothelial growth factor receptor 2 (VEGFR2) contributes to tamoxifen resistance in estrogen-positive breast cancer patients. Mol Biol 55:118–125
Coltelli L, Allegrini G, Orlandi P, Finale C, Fontana A, Masini LC et al (2022) A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients. NPJ Breast Cancer 8:33–42
Butkiewicz D, Gdowicz-Kłosok A, Krześniak M, Rutkowski T, Krzywon A, Cortez AJ et al (2020) Association of genetic variants in ANGPT/TEK and VEGF/VEGFR with progression and survival in head and neck squamous cell carcinoma treated with radiotherapy or radiochemotherapy. Cancers 12:1506–1524
Yan Z, Gu YY, Hu XD, Zhao Q, Kang HL, Wang M et al (2020) Clinical outcomes and safety of apatinib monotherapy in the treatment of patients with advanced epithelial ovarian carcinoma who progressed after standard regimens and the analysis of the VEGFR2 polymorphism. Oncol Lett 20:3035–3045
Loupakis F, Cremolini C, Yang D, Salvatore L, Zhang W, Wakatsuki T et al (2013) Prospective validation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. PLoS ONE 8:e66774
Garcia-Donas J, Esteban E, Leandro-García LJ, Castellano DE, González del Alba A, Climent MA et al (2011) Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 12:1143–1150
Kim MK, Suh C, Chi HS, Cho HS, Bae YK, Lee KH et al (2012) VEGFA and VEGFR2 genetic polymorphisms and survival in patients with diffuse large B cell lymphoma. Cancer Sci 103:497–503
Kaddu-Mulindwa D, Rosolowski M, Ziepert M, Regitz E, Assmann G, Bewarder M et al (2021) VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma. Eur J Haematol 106:100–104
Alagele MH, Alwash MM, Ahmed AA (2020) Vascular endothelial growth factor receptor 2 (VEGFR2) gene polymorphism and treatment outcome following imatinib therapy in Iraqi patients with chronic myeloid leukemia. Eur J Mol Clin Med 7:4847–4857
Fazio N, Martini JF, Croitoru AE, Schenker M, Li S, Rosbrook B et al (2019) Pharmacogenomic analyses of sunitinib in patients with pancreatic neuroendocrine tumors. Future Oncol 15:1997–2007
van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP et al (2011) Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 17:620–629
Dornbusch J, Walter M, Gottschalk A, Obaje A, Junker K, Ohlmann CH et al (2016) Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients. J Cancer Res Clin Oncol 142:1171–1182
Gal J, Milano G, Brest P, Ebran N, Gilhodes J, Llorca L et al (2020) VEGF-related germinal polymorphisms may identify a subgroup of breast cancer patients with favorable outcome under bevacizumab-based therapy-A message from COMET, a French unicancer multicentric study. Pharmaceuticals (Basel) 13:414–426
Acknowledgements
We would like to thank the study participants for taking part in the present study. This work was supported by the MHRD grant under RUSA scheme sanctioned to Dr. Kamlesh Guleria and Prof. (Dr.) Vasudha Sambyal.
Funding
As funding for this study, the authors received the MHRD grant under RUSA scheme.
Author information
Authors and Affiliations
Contributions
KG and VS designed the study. SKW performed the experiments and analyzed the data. SKW and KG prepared the manuscript. MSU and MS did clinical diagnosis of patients and also helped in collection of blood samples of patients. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Guru Nanak Dev University, Amritsar, Punjab (India). Informed consent was obtained from all individual participants included in the present study.
Competing interests
All the authors declare that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Walia, S.K., Sambyal, V., Sudan, M. et al. Association of VEGFR1, VEGFR2 and VEGFR3 polymorphisms with esophageal cancer risk: a case–control study. Egypt J Med Hum Genet 25, 93 (2024). https://doi.org/10.1186/s43042-024-00564-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s43042-024-00564-9