Study On The Association Of VEGF Genetic Polymorphisms With Primary Lung Cancer

Objective：Carcinoma of the lung has became the leading cause ofdeath due to cancer worldwide. The disease has become an epidemic asincidence rates and lung cancer deaths have risen dramatically over thelast century, correlating with an increase in cigarette consumption. Morethan1.5million new cases of lung cancer are now diagnosed annuallyworldwide, while lung cancer was considered an extremely raremalignancy in the early20th century.In China, lung cancer now hasbecome the leading cause of cancer death. Over the past30years, lungcancer mortality increased by465%.The investigation of countries showsthat the etiology of lung cancer and smoking cigarettes is extremely closerelationship。The incidence of lung cancer in smoker is10times higherthan non-smokers. But in the same exposure to tobacco, only less than20%smokers develop in to lung cancer,that suggests that differentgenetic factors may influence the occurrence of lung cancer.Individualshave a genetic susceptibility to lung cancer. With the rapid developmentof molecular biology, the study of the genetic level is also increasing.Tumor cells have an absolute requirement for a persistent supply ofnew blood vessels to nourish their growth and to facilitate metastasis.Thus, tumor vascularization is a vital process for the progression of aneoplasm from a small localized tumor to an enlarging tumor with theability to metastasize. VEGF, the most potent direct-acting angiogenicprotein known，is a diffusible endothelial cell-specific mitogen andangiogenic factor that also increases vascular permeability. Malignanttransformation of cultured cells often results in an induction of VEGFexpression. VEGF is highly expressed in lung cancer tissue. Studies havealso shown that, VEGF is a main index to judge the prognosis of lung cancer.The gene encoding VEGF is located on chromosome6andcomprises a14-kb coding region with8exons and7introns. Severalpolymorphisms have been described in the VEGF gene. Thepolymorphisms in the promoter region [loci2578C/A and460T/C],5′-untranslated region (UTR)[+405G/C] or3′-UTR [+936C/T] have beenassociated with different levels of VEGF expression. We conducted acase-control tu investigate the role of VEGF gene promoterregion-2578C/A single nucleotide polymorphism in relation to lungcancer risk.Methods：In this case-control experiment, the Chinese Hanpopulation of260patients with lung cancer and260healthy controlswere studied. Lung cancer patients were all pathologically confirmed.Genomic DNA was isolated from whole blood by using proteinase Kdigestion followed by a salting out procedure. Genotypes of the-2578C/ASNPs were analyzed by polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) method and primer introducedrestriction analysis PCR (PIRA-PCR). Statistical analysis was analysisedby using SPSS13.0version software package. A probability level of5%was considered significant.Resuls：1Gender, age composition between lung cancer patients and healthycontrol group had no significant difference（p＞0.05）.2The frequency of smokers in lung cancer patients and healthycontrols were59.6%/41.3%, respectively. There was statisticallysignificant difference between the patients and controls(χ2=8.370，p＜0.01）.Smoking may increased the risk of developing lung cancer（OR=2.321，95%CI=1.543-4.653).3The proportion of a family history in Lung cancer group wassignificantly higher than controls group.（χ2=6.734，p＜0.01）. Thatshows that family history can significantly increase the risk of lung cancer(OR=1.321，95%CI=1.007-1.724).4The genotype frequencies of the VEGF-2578C/C, C/A and A/A inpatients and controls were48.5%,45.7%å'Œ5.8%ï¼›62.3%,34.5%å'Œ3.2%,respectively; the C and A allele frequencies were73.7%,26.7%and79.3%,20.7%, respectively. There was statistically significant differencein the genotype distributions or allele frequencies of VEGF-2578C/Abetween the patients and controls (p=0.007). Compared with theC/C+C/A genotypes, the A/A genotype could significantly modify therisk of developing epithelial ovarian cancer. The odds ratio was2.044(95%CI=1.394~2.994).5Stratification analysis according to histological type showed thatcompared with C/C genotype, the combination of C/A and A/A genotypeincreased the risk of adenocarcinoma and Squamous cell carcinoma (age,gender and smoking status adjusted OR=1.321and1.264,95%CI=1.210-1.875and1.060-1.982,respectively). When stratified bysmoking status and family history, compared with the C/C genotype, thecombination of C/A and A/A genotype increased the risk of lung cancer insmokers and people with family history(age and gender adjustedOR=2.321,1.321,95%CI=1.543-4.653,1.007-1.724, respectively).Conclusion：1Smoking may increased the risk of developing lung cancer.2Family history can significantly increase the risk of lung cancer.3VEGF-2578C/A polymorphism was associated with susceptibilityto lung cancer, carrying A allele（C/A+A/A） may significantly increasethe risk of developing lung cancer.4The combination of C/A and A/A genotype increased the risk oflung cancer in smokers and people without a family history of tumor. Thecombination of C/A and A/A genotype associated with lymph nodemetastasis and tumor stage.