| 1. BACKGROUD AND OBJECTIVEEsophageal cancer (EC) is one of the most sixth common malignancies worldwide, as well as the fourth most frequent cause of cancer-related deaths in China. Esophageal carcinogenesis has been considered as a multistep progressive process, both environment and heredity factors play all important part in this process. The role of various carcinogenic factors among the environment could change the structure and function of DNA for esophageal epithelial cell. In this process of different stages, there may be multiple genes alter and which are worked in diverse phases, and may occur biological changes variously. Between theirs each other, more or less the two aspects have different effects. Chronic esophagitis (CE) provides a microenvironment for esophageal mucosa epithelial carcinogenesis.Our previous study have identified two important susceptibility genes of esophageal squamous cell carcinoma (ESCC) using genome-wide association study (GWAS), phospholipase C epsilon 1 (PLCE1) and chromosome 20 opening reading frame 54 (C20orf54). Among them, PLCE1 play a crucial role on adjusting epithelial cells about hyperplasia, differentiation, apoptosis and regeneration, and C20orf54 is the riboflavin (7,8-dimethyl-10-ribityl-isoalloxazine) transporter gene which plays an important role in the intestinal absorption of riboflavin.The purpose of this study is to analyse the CE characteristics and the relation between CE and EC and further explain the lesion process and pathogenesis of them, and provide certain genetic basis and molecular targets for establishing the screening of esophageal cancer high-risk population, early diagnosis and treatment, individual prevention strategy. The way is showed by analyzing the epidemiological characteristics of CE in high/low incidence area (HIA/LIA) and researching single-nucleotide polymorphisms (SNPs) of PLCE1 and C20orf54 genes to the risk of CE from molecular level analysis through using GWAS.2. SUBJECTS AND METHODS2.1 SubjectsAll the subjects were collected from the large scale of mass survey and follow-up outpatient of gastroscope from 2008 to 2011 as below:Anyang City Tumor Hospital of Henan Province, Cixian People Hospital of Hebei Province and Changzhi City Peace Hospital of Shanxi Province, et al. the HIA for EC, and Shangqiu City People Hospital, Puyang City People Hospital, Xinyang City People Hospital of Henan Province, et al. the LIA for EC.2.2 Epidemiological investigation and genotype determination2.2.1 All respondents (32833 cases) mainly uses the outpatient service questionnaire survey, part of the household survey and follow-up methods to collect name, gender, age, family history, domicile of origin, etc. all the general information and obtained clear diagnosis through electronic gastroscope inspection.2.2.2 The genotypes of SNP rs2274223 and rs13042395 (gained through the internationally recognized chip of Illumina 610-Quad BeadChips Human SNP) of 725 cases of CE patients and 2187 cases normal controls were used for analyzing.2.3 Data collection and filingAll results were filed adopting Excel and software processing for data entry. And further confirm the information of gastroscope inspection and pathological diagnosis, and collect the relevant material (including clinical background and contact information, etc.) through consulting the patients' clinical files and follow-up partly.2.4 Collection and processing of blood specimensOn the premise of issued informed consent for outpatients, fasting peripheral venous blood was collected,5ml from one person one time and anticoagulant treatment on-site each time, then sent this samples to the laboratory for experiment or store in -40℃/-80℃frozen refrigerator for using later.2.5 Statistical methodTo determine whether exist selective differences between the case group and control group, balance test of populations was performed by statistical method. All the data were analyzed by using the SPSS 17.0 software, chi-square test analysis for each variable, inspection significant level take as 0.05, and P value below 0.05 as significance. And multi-factor unconditional Logistic regression analysis (the standard of opt-in and opt-out variables is 0.05 and 0.10, respectively) was applied, to research different factors whether have effect on the risk to CE from molecular level.3. RESULTS3.1 Chronic esophagitis detection rateCE detection rate is 9.78%(3203/32833). The HIA detection rate of CE is 10.98%(1065/9702) slightly higher than that's 9.24%(2138/23131) in LIA (P= 1.35E-6,χ2=23.35, OR=1.21,95%CI [1.12-1.31]). The HIA detection rate of severe CE is 7.68%(745/9702) significantly higher than that's 1.25%(289/23131) in LIA (P =1.83E-203,χ2=926.35, OR=6.57,95%CI [5.73-7.55]).3.2 Chronic esophagitis gender and age distribution3.2.1 Gender proportion of CE about male and female is 64.06%(2052/3203) and 35.94%(1151/3203), respectively. All CE patients have an average age of 52±12 years old, the age range is from 16 to 84 years old, sicken age is mainly from 40 to 60 years old (57.70%).3.2.2 The gender distribution of CE is predominantly male with HIA (male,63.10%; female,36.90%) and LIA (male,64.55%; female,35.45%). There were no significant difference between genders in HIA and LIA (P=4.21E-1,χ2=0.65, OR=0.94, 95%CI [0.81-1.10]).3.2.3 The average age of CE in HIA and LIA is 54±11 and 51±12 years old, age range is from 18 to 84 and from 16 to 83 years old, respectively, both of which have significant difference (P=3.59E-4) in average age. The sicken age of CE in HIA and LIA is concentrate from 40 to 60 years old (60.37% and 56.36%, respectively). There is a statistically significant difference in age distribution of CE between HIA and LIA (P=1.11E-8).3.3 Gene polymorphism and chronic esophagitis3.3.1 Total distribution of genotype and allele has statistically significant in rs2274223 and rs13042395 between cases and controls (P=5.30E-3,χ2=10.48 and P=1.72E-3,χ2=9.83, OR=1.25,95%CI [1.09-143]; P=4.62E-2,χ2=6.15 and P= 4.91E-2,χ2=3.87, OR=1.14,95%CI [1.00-1.31]).3.3.2 Genotype distribution was no statistically significant in rs2274223 and rs13042395 between HIA and LIA CE patients (Punadjusted=9.47E-1, Padjusted 9.26E-1,χ2=0.11;Punadjusted=1.68E-1, Padjusted=6.67E-2,χ2=3.57).3.3.3 Between cases and controls in rs2274223 and rs13042395 loci, logistic regression analysis results indicated there was statistically significant in genotype distribution of rs2274223 locus (P=1.09E-2,χ2=6.47, OR=1.52,95%CI [1.10-2.14]), however, there was no statistically significant in genotype distribution of rs13042395 locus (P=5.66E-1,χ2=0.37, OR=1.11,95%CI [0.80-1.53]).3.4 Chronic esophagitis dangerous factor analysisComprehensive evaluation of logistic regression analysis showed that the dangerous factors of having CE were male, age from 40 to 60 years old and HIA, and gene mutations of PLCE1 increased the risk to CE.4. CONCLUSIONS4.1 The incidence of CE in HIA is higher than LIA. The gender distribution shows males get CE easier than females. The population among 40 and 60 tend to get CE.4.2 The susceptibility to CE is correlation with PLCE1 genetic polymorphism, and no correlation with C20orf54 genetic polymorphism. 4.3 Logistic regression analysis results indicate that CE is closely related with gender, age and incidence area. |
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