In the present study we have investigated the association of VEGFR1 -710C/T, VEGFR2 -604T/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 (Rodrigues et al. 2012), whereas no association of VEGFR1 -710C/T polymorphism with breast cancer risk has been reported in patients from Punjab North-West India (Kapahi et al. 2015).
The promoter polymorphism VEGFR2 -604T/C changes the binding site for transcription factor E2F in KDR promoter region, which can down regulate KDR expression (Wang et al. 2007). In the present study, TC genotype of VEGFR2 -604T/C polymorphism was significantly associated with reduced risk of esophageal cancer. The TC + CC combined genotype of VEGFR2 -604T/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 (Jang et al. 2013). The C allele of VEGFR2 -604T/C polymorphism was associated with increased risk of pancreatic cancer in Romanian population (Padureanu et al. 2017). However, no correlation of VEGFR2 -604T/C polymorphism has been observed with gastric cancer (Zhu et al. 2019) and hepatocellular carcinoma in Chinese population (Wang et al. 2014). In Danish population, TT + TC genotype of VEGFR2 -604T/C was associated with improved overall survival in colorectal cancer patients (Hansen et al. 2010).
VEGFR2 1192G/A polymorphism located in third NH2 terminal Ig- like domains in the extracellular region, is crucial for ligand binding (Wang et al. 2007). 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 (Jang et al. 2013). In Danish population, GG genotype of VEGFR2 1192G/A polymorphism was associated with improved survival in patients having colorectal cancer (Hansen et al. 2010). GA genotype was associated with lower overall survival in hepatocellular cancer Han Chinese patients (Wang et al. 2014). No correlation was observed between VEGFR2 1192G/A polymorphism and gastric cancer in Chinese population (Zhu et al. 2019).
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 (Lurje et al. 2010). Similarly, no association of VEGFR2 1719A/T polymorphism has been reported in hepatocellular carcinoma in Han Chinese (Wang et al. 2014) and colorectal cancer in Danish patients (Hansen et al. 2010). The T allele of VEGFR2 1719A/T polymorphism was associated with increased hepatocellular cancer risk in Portuguese patients (Machado et al. 2014), whereas AA genotype was associated with poor prognosis in Chinese gastric cancer patients (Zhu et al. 2019).
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 (Qin et al. 2016) and sunitinib (Liu et al. 2017) 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 (Jang et al. 2013). The response of VEGFRs polymorphisms with different therapies in GIT cancers has been studied in different populations and reported association with disease survival (Supplementary Table 5–7).
In the present study, we found that VEGFR1 -710C/T, VEGFR2 -604T/C and VEGFR2 1192G/A polymorphisms were associated with the decreased risk of esophageal cancer in the patients from Punjab, North-West India. Further studies on different ethnic groups are required to evaluate the association between VEGFRs polymorphisms and esophageal cancer.