Original Article| Volume 130, ISSUE 5, P557-564, November 2020

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Single nucleotide polymorphisms and serologic levels of hypoxia-inducible factor1 α and vascular endothelial growth factor are associated with increased risk of oral submucous fibrosis in gutka users among a North Indian population

Published:September 25, 2020DOI:


      Tissue hypoxia in oral submucous fibrosis (OSMF) induces hypoxia-inducible factor (HIF)-1 α and vascular endothelial growth factor (VEGF), causing angiogenesis. Single nucleotide polymorphisms (SNPs) may predict susceptibility to environmental carcinogens and to development of OSMF, as well as its severity and malignant transformation. This study aimed to determine the serologic levels and frequencies of SNPs of HIF-1 α and VEGF in OSMF.

      Study Design

      In this prospective pilot study, the frequencies of SNPs of HIF-1 α (C1772 T, G1790 A); VEGF-A 936 C/T; and VEGF-C (rs7664413, rs1485766) in patients with OSMF or oral squamous cell carcinoma (OSCC) and in healthy controls were determined by using polymerase chain reaction (PCR) (n = 100 each), and serologic levels were determined by using enzyme-linked immunosorbent assay (ELISA (n = 50 each), in a North Indian population.


      Heterozygous forms of HIF-1 α C1772 T (CT: odds ratio [OR] 5.0; 95% confidence interval [CI] 2.24–11.16; P < .001); HIF-1 α G1790 A (GA: OR 2.8; 95% CI 1.62–5.16; P < .001); and VEGF-C rs1485766 (AC: OR 2.18; 95% CI 1.19–3.99; P < .05) were associated with OSMF. The mean serologic levels of HIF-1 α, VEGF-A, and VEGF-C were significantly raised in patients with OSMF compared with healthy controls (P < .001).


      The SNPs of HIF-1 α, VEGF-A, and VEGF-C and their serologic levels can act as prognostic biomarkers and aid in the development of specialized anti-HIF-1 α or anti-VEGF drugs for the management and prevention of OSCC in patients with OSMF.
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        • Neville B.W.
        • Damm D.D.
        • Allen C.M.
        • et al.
        Epithelial pathology.
        in: Neville B.W. Damm D.D. Allen C.M. Oral and Maxillofacial Pathology. 2nd ed. WB Saunders, Philadelphia, PA2002: 315-387
        • Nigam N.K.
        • Aravinda K.
        • Dhillon M.
        • Gupta S.
        • Reddy S.
        • Srinivas Raju M.
        Prevalence of oral submucous fibrosis among habitual gutkha and areca nut chewers in Moradabad district.
        J Oral Biol Craniofac Res. 2014; 4: 8-13
        • Pindborg J.J.
        • Sirsat S.M.
        Oral submucous fibrosis.
        Oral Surg Oral Med Oral Pathol. 1966; 22: 764-779
        • Murti P.R.
        • Bhonsle R.B.
        • Pindborg J.J.
        • Daftary D.K.
        • Gupta P.C.
        • Mehta F.S.
        Malignant transformation rate in oral submucous fibrosis over a 17-year period.
        Community Dent Oral Epidemiol. 1985; 13: 340-341
        • Chourasia N.R.
        • Borle R.M.
        • Vastani A.
        Concomitant association of oral submucous fibrosis and oral squamous cell carcinoma and incidence of malignant transformation of oral submucous fibrosis in a population of central India: a retrospective study.
        J Maxillofac Oral Surg. 2015; 14: 902-906
        • Ray J.G.
        • Ranganathan K.
        • Chattopadhyay A.
        Malignant transformation of oral submucous fibrosis: overview of histopathological aspects.
        Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 122: 200-209
        • Jiang J.-W.
        • Chen X.-W.
        • Yao Q.-H.
        • Zhang H.
        Research progress in arecoline-induced oral submucous fibrosis.
        Food Therapy and Health Care. 2019; 1 ( 97-101
        • Li Y.-C.
        • Cheng A.-J.
        • Lee L.-Y.
        • Huang Y.-C.
        • Chang J.T.-C.
        Multifaceted mechanisms of areca nuts in oral carcinogenesis: the molecular pathology from precancerous condition to malignant transformation.
        J Cancer. 2019; 10: 4054-4062
        • Yan Q.
        • Chen P.
        • Wang S.
        • Liu N.
        • Zhao P.
        • Gu A.
        Association between HIF-1 α C1772 T/G1790 A polymorphisms and cancer susceptibility: an updated systematic review and meta-analysis based on 40 case-control studies.
        BMC Cancer. 2014; 14: 950
        • Zhou Y.
        • Lin L.
        • Wang Y.
        • et al.
        The association between hypoxia-inducible factor-1 α gene G1790 A polymorphism and cancer risk: a meta-analysis of 28 case-control studies.
        Cancer Cell Int. 2014; 14: 37
        • Shieh T.-M.
        • Chang K.-W.
        • Tu H.-F.
        • et al.
        Association between the polymorphisms in exon 12 of hypoxia-inducible factor-1 α and the clinicopathological features of oral squamous cell carcinoma.
        Oral Oncol. 2010; 46: e47-e53
        • Tilakaratne W.M.
        • Iqbal Z.
        • Teh M.T.
        • et al.
        Upregulation of HIF-1 alpha in malignant transformation of oral submucous fibrosis.
        J Oral Pathol Med. 2008; 37: 372-377
        • Chien M.-H.
        • Liu Y.-F.
        • Hsin C.-H.
        • et al.
        Impact of VEGF-C gene polymorphisms and environmental factors on oral cancer susceptibility in Taiwan.
        PLoS One. 2013; 8: e60283
        • Sharada P.
        • Swaminathan U.
        • Nagamalini B.R.
        • Kumar K.V.
        • Ashwini B.K.
        • Lavanya V.
        Coalition of E-cadherin and vascular endothelial growth factor expression in predicting malignant transformation in common oral potentially malignant disorders.
        J Oral Maxillofac Pathol. 2018; 22: 40-47
        • Borase A.P.
        • Ganvir S.M.
        • Hazarey V.K.
        • Gosavi S.R.
        • Mohatta A.A.
        • Singh J.
        Estimation of vascular endothelial growth factor gene -460 C/T polymorphism as a biomarker in oral squamous cell carcinoma patients from the Indian subcontinent.
        J Investig Clin Dent. 2015; 6: 267-272
        • Rai D.V.
        • Guttal K.S.
        • Kulkarni B.B.
        • Hiremath S.
        • Burde K.N.
        Vascular endothelial growth factor (VEGF) gene polymorphism in oral submucous fibrosis subjects—a preliminary study.
        Asian J Med Sci. 2016; 7: 10-16
        • Venkatesh D.
        • Puranik R.S.
        • Vanaki S.S.
        • Puranik S.R.
        Study of salivary arecoline in areca nut chewers.
        J Oral Maxillofac Pathol. 2018; 22: 7
        • Muñoz-Guerra M.F.
        • Fernández-Contreras M.E.
        • Moreno A.L.C.
        • Martín I.D.
        • Herráez B.
        • Gamallo C.
        Polymorphisms in the hypoxia inducible factor 1-α and the impact on the prognosis of early stages of oral cancer.
        Ann Surg Oncol. 2009; 16: 2351-2358
        • Yapijakis C.
        • Vairaktaris E.
        • Vassiliou S.
        • et al.
        The low VEGF production allele of the +936 C/T polymorphism is strongly associated with increased risk for oral cancer.
        J Cancer Res Clin Oncol. 2007; 133: 787-791
        • Xu B.
        • Li J.-M.
        • Tong N.
        • et al.
        VEGFA + 936 C>T polymorphism and cancer risk: a meta-analysis.
        Cancer Genet Cytogenet. 2010; 198: 7-14
        • Warnakulasuriya S.
        • Johnson N.W.
        • van der Waal I.
        Nomenclature and classification of potentially malignant disorders of the oral mucosa.
        J Oral Pathol Med. 2007; 36: 575-580
        • More C.B.
        • Das S.
        • Patel H.
        • Adalja C.
        • Kamatchi V.
        • Venkatesh R.
        Proposed clinical classification for oral submucous fibrosis.
        Oral Oncol. 2012; 48: 200-202
        • Li Y.
        • Li C.
        • Shi H.
        • Lou L.
        • Liu P.
        The association between the rs11549465 polymorphism in the hif-1 α gene and cancer risk: a meta-analysis.
        Int J Clin Exp Med. 2015; 8: 1561-1574
        • de Fraga C.A.C.
        • de Oliveira M.V.M.
        • de Oliveira É.S.
        • et al.
        A high HIF-1 α expression genotype is associated with poor prognosis of upper aerodigestive tract carcinoma patients.
        Oral Oncol. 2012; 48: 130-135
        • Cheng C.-Y.
        • Chang C.-S.
        • Liu C.-J.
        • Kao S.-Y.
        Vascular endothelial growth factor 936 C/T polymorphism is associated with vascular invasion in oral squamous cell carcinoma.
        Oral Surg Oral Med Oral Pathol, Oral Radiol Endod. 2008; 106: 79-84
        • Cao C.
        • Fang J.-J.
        • Ying T.
        • et al.
        Vascular endothelial growth factor +936 C/T and +405 G/C polymorphisms and cancer risk: a meta-analysis.
        Arch Med Res. 2010; 41: 548-557
        • Mandal R.K.
        • Yadav S.S.
        • Panda A.K.
        • Khattri S.
        Vascular endothelial growth factor 936 C>T polymorphism increased oral cancer risk: evidence from a meta-analysis.
        Genet Test Molecular Biomarkers. 2013; 17: 543-547
        • Kämmerer P.W.
        • Toyoshima T.
        • Eletr S.
        • et al.
        Single nucleotide polymorphisms of the vascular endothelial growth factor gene associated with incidence of oral squamous cell carcinoma.
        J Oral Pathol Med. 2010; 39: 786-792
        • Metzger C.S.
        • Kämmerer P.W.
        • Schmidtmann I.
        • Brieger J.
        Vascular endothelial growth factor polymorphisms as effect modifiers of oral squamous cell carcinoma risk: a systematic review and meta-analysis.
        Mol Clin Oncol. 2015; 3: 347-352
        • Supic G.
        • Jovic N.
        • Zeljic K.
        • Kozomara R.
        • Magic Z.
        Association of VEGF-A genetic polymorphisms with cancer risk and survival in advanced-stage oral squamous cell carcinoma patients.
        Oral Oncol. 2012; 48: 1171-1177
        • Chaturvedi P.
        • Vaishampayan S.S.
        • Nair S.
        • et al.
        Oral squamous cell carcinoma arising in background of oral submucous fibrosis: a clinicopathologically distinct disease.
        Head Neck. 2013; 35: 1404-1409