| 1Background and purposeJapanese researchers found that rs671sites gene mutation located in aldehyde dehydrogenase2(ALDH2) are closely related with a high risk of esophageal cancer. ALDH2gene mutation leads to blocking degradation process of acetaldehyde in the normal metabolism of ethanol, and accumulating in the blood, resulting after drinking blush. The relationship of alcohol flushing, ALDH2gene mutation and cancer incidence risk are concerned because of this discovery, but the findings are not consistent, which may be associated with different tumors, different populations. It is unclear that the relationship of rs671sites gene mutation located in ALDH2, flush and drinking with esophageal cancer risk and prognosis in Chinese people. This topic prode the relationship of flush, flush family history, drinking and rs671sites gene mutation and their impact on the risk and prognosis of esophageal cancer through case-control study, in order to provide early warning indicators and screening and prognosis methods of esophageal cancer in high-risk populations.2Materials and Methods2.1SubjectsStudy subjects were from Henan Province Key Laboratory of esophageal cancer information database. The case group was from esophageal cancer hospitalized patients from1975to2012. All patients were pathologically diagnosed as esophageal squamous cell carcinoma(ESCC). The control group was from the normal population in the same period and regions. All people in the control group were examined by transesophageal endoscopic to exclude upper gastrointestinal tumors. The case group was3759, of which3,030were male and mean age was59.1±8.7, and729were female and mean age was60.6±9.4. The control group was5196, of which3,447were male, mean age was47.5±12.4and1749were female, mean age was49.1±11.8.2.2Standard of Alcohol Flushing, Drinking and SmokingAlcohol Flushing:facial flushing after small amount of alcohol (50ml) in a short appearance. Not Drinking means never drinking or occasionally drinking(no more than three times a year and each no more than50ml), and Not Smoking means never smoking or occasional smoking (no more than three cigarettes a year), otherwise recorded as drinking and smoking.2.3QuestionnairesIn the village or hospital, the patient/family member/village doctors were conducted a questionnaire survey included general, flush, flush family history, smoking, drinking, family history of cancer, treatment, etc. The survey number of patients in flushing, drinking and smoking was3759(100%),3651(97%) and3,653cases (97%); the control group was5040(97%),5196(100%) and5,146cases (99%). 2.4Clinical and pathological data collectionHospital medical records were picked out in accordance with the information of questionnaire survey and conducted verification and supplement of clinical pathology information.2.5Follow-upFollow-up was from the date of the survey to patients death and last follow-up time was in Nov.2013.2645patients (90.6%)were successful follow-up in2921patients with accurate home address, telephone number clearly.2.6Blood samples, DNA extraction and Taqman genotypingAfter each patient and normal controls detailed questionnaire, each people signed informed consent and was collected5ml peripheral venous blood into EDTA anticoagulated,-20℃stored. Using the German Qiagen Flexi Gene DNA extraction kit to extract the PWBC genomic DNA. Using Taqman(?) genotyping technology to detect ALDH2rs671gene locus genotypes.2.7Statistical analysisAll data were statistically analyzed using SPSS19.0. All data were analyzed with χ2test, Logistic Regression, life-table method, Kaplan-Meier method, Cox model,etc. Inspection standards:α<0.05.3Results3.1Flushing, flush family history, drinking, smoking with esophageal cancer riskEsophageal cancer risk had increased in people with flushing and flushing family history positive, drinkers and smokers (OR values were1.26,1.23,2.11,1.47;95%CI were1.14-1.38,0.79-1.90,1.93-2.30,1.35-1.60; P values were1.33E-6,0.36,4.56E-65,7.87E-19). After drinking and flushing superimposed, flushing and nondrinkers had ESCC highest risk (OR=2.33,95%CI:2.01-2.71; P=4.01E-28). After flushing, drinking and smoking superimposed, people with smoking, dringking and not flushing had ESCC highest risk (OR=3.17,95%CI:2.61-3.86; P=2.89E-31).3.2The relationship of flushing and rs671gene locus mutationrs671gene locus mutation frequency of flushing was higher19.4%than not flushing (χ2=47.25, P=6.24E-12). rs671gene locus mutation frequency of flushing and not flushing patients were85(33.6%) and76(19.9%)(χ2=15.10, P=1.00E-4). rs671gene locus mutation frequency of flushing and not flushing in control group were133(32.3) and71(15.5%)(χ2=34.07,P=5.23E-9). There was no difference in the distribution of pathological information stratified analysis in patients with flushing and not flushing, rs671sites of wild-type and mutant.3.3Flushing and rs671locus mutation with survival analysis of patients with esophageal cancerThe survival of flushing patients with esophageal cancer was better than not flushing patients (χ2=5.10, P=0.02). According to the high incidence, men, BMI normal, non-drinkers, the lower esophagus, Tis, without lymph node metastasis, poorly differentiated and undifferentiated, tumor diameter<4cm, medullary, early and middle ESCC and other factors stratified analysis, the survival of flushing patients with esophageal cancer was better than not flushing patients in each level.rs671sites of wild-type and mutant had no difference in survival (χ2=0.18, P=0.68). According to clinical and pathological information stratified analysis, rs671sites of wild-type and mutant had no difference in survival in each level.3.4Cox modelAge of onset, high-low incidence area, BMI and lymph node metastasis were independent risk factors for ESCC (P values were0.001,1.85E-5,0.04,8.78E-6).4Conclusion4.1The risk of esophageal cancer with drinking and flushing significantly increase;4.2Flushing associated with rs671locus mutation; 4.3The survival of flushing patients with esophageal cancer is better than not flush patients; however, the survival of ALDH2gene with the wild-type and mutant has no difference;4.4Age of onset, high-low incidence area, BMI and lymph node metastasis are independent risk factors for esophageal cancer. |
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