Role Of ERCC1 And ERCC2 Genetic Polymorphisms In The Gastric Cancer Susceptibility And Prognosis Of Gastric Cancer Patients Receiving Oxaliplatin-based Chemotherapy

Chapter I:ERCC1 and ERCC2 gene polymorphisms related to the susceptibility of gastric cancerBackground and objective:.Due to the symptoms of early gastric cancer is relatively hidden,clinical often characterized by loss of appetite Abdominal pain Abdominal distension and body weight and so on,these symptoms often ignored,resulting in diagnosis of gastric cancer,and mostly in the middle-late and distant metastasis,so even if the use of surgery and postoperative chemoradiation,stomach cancer mortality is higher For late postoperative recurrence and metastasis of gastric cancer patients,lost the best operative opportunity,can only accept systemic chemotherapy,at this time,the prognosis of patients with gastric cancer,chemotherapy has become the main method of treatment.Platinum is the basis of the treatment of stomach cancer drugs,from the first generation of cisplatin The second generation of platinum CARDS as well as the third generation of oxaliplatin into a gradual development process Oxaliplatin into(platinum,oxalate LOHP)after cisplatin and carboplatin is the third generation of platinum antitumor drugs,curative effect is better,the characteristics of oxaliplatin into lower toxicity,the efficacy and toxicity of drug is bigger improvement,and expand the antineoplastic spectrum,and there is no cross resistance to drugs and cisplatin and carboplatin.Clinical research results show that the early use of oxaliplatin into monotherapy and the curative effect of gastric cancer is 22%,with 5 fluorouracil(5 FU)and the curative effect of calcium leucovorin(LV)scheme close to with 5-FU and oxaliplatin into LV combination drug sensitivity can reach 60%nucleic acid excision repair pathways of gene expression in the single nucleotide polymorphism can lead to the change of the DNA repair ability,which lead to amino acids code changes and SNP in particular are likely to change in gene regulation region repair enzyme activity or express the amount of difference,which affects the DNA repair capability.Nucleic acid excision repair way of ERCC1 and ERCC2 gene polymorphism may affect protein function,including DNA damage recognition and shear damage DNA adduct of nucleotide excision repair and base transcription repair mechanism,which leads to the instability of DNA,ultimately affect the DNA repair function When cancer patients undergoing chemotherapy,effective damage cancer cells,such as DNA repair function in patients with increased,such as platinum chemotherapy drugs cancer cell damage repair in time,to produce drug resistance,but when the DNA repair function to reduce damage in platinum chemotherapy drugs such as cancer cells to repair activity is reduced,so the platinum chemotherapy drug sensitivity,etc So presumably ERCC1 and ERCC2 gene polymorphism can affect the sensitivity of the patients with platinum drugs chemotherapy,ultimately affect the prognosis of patients.Methods:In March 2010-March 2013,the people in Inner Mongolia medical university affiliated hospitals accept pathology confirmed 185 cases of advanced gastric cancer patients with gastric cancer for cases(male 124 cases,accounting for 67.03%;female 61 cases,accounting for 32.97%;the average age of 58.79 58.79 years),adopt the way of face to face questionnaire survey collects information on research object,and extract the respondents peripheral venous blood of 5 ml,using ethylenediamine tetraacetic acid dipotassium antithrombotic treatment(EDTA-K2)and stored under test Once a month of follow-up,in patients with gastric cancer in gastric cancer death as the end of time,the telephone follow-up or outpatient care follow-up,record the patient’s cancer progression and death.All patients were followed up in March 2015,according to RECIST criteria,assessment of the effect of the treatment of ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs 1799793 gene polymorphism detection using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)method after reaction,the product will take 10 mu 1 used for preliminary analysis,placed on a 3%agarose gel electrophoresis and analysis system of spare specificity and the result is acceptable to save the rest of the preparation of the product of in-20 using SPSS 19.0(version 19.0,SPSS Inc.,Chicago,IL,USA),statistical analysis,all the statistical tests are bilateral inspection,inspection level take alpha was 0.05.Results:The Log-rank test methods,the following lifestyle and eating habits survival difference was statistically significant,patients with history of drinking(Log-rank test = 6.44,P = 0.011)with or without family history of malignancy(Log-rank test = 6.21,P = 0.013),the sensitivity of chemotherapy(Log-rank test = 48.98,P<0.001)ERCC1 rs11615 and ERCC2 rs 1799793 gene frequency distribution accord with Hardy-Weinberg,genetic balance,but ERCC1 rs3212986 and ERCC2 rs13181B does not conform to the Hardy-Weinberg genetic equilibrium.By multiariable logistic regression,after adjustment for age and gender factors,the results show that carry ERCC1 rs11615 TT genotype individuals and carry ERCC1 rs11615 CC genotype individuals compared to patients with cancer of the stomach show is sensitive to platinum chemotherapy drug resistance(OR = 0.27,95%CI =0.08 0.96)carry ERCC1 rs11615 CT + TT genotype individuals and carry ERCC1 rs11615 CC genotype individuals compared to patients with cancer of the stomach to platinum chemotherapy sensitive resistance(OR ＝ 0.45,95%CI = 0.23-0.90).However,ERCC1 rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphism does not affect the sensitivity of the gastric cancer patients with chemotherapy(P>0.05)using COX regression analysis and Log-rank analysis found that did not find ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs 1799793 gene polymorphism and gastric cancer patients’ survival time and the risk of death.Conclusion:Study found that carry ERCC1 rs11615 TT gene or carrying CT + TT genotype individuals and carry ERCC1 rs 11615 CC genotype,compared to individual patients with gastric cancer showed on platinum chemotherapy sensitivity in drug resistance However ERCC1 rs3212986 and ERCC2 rs13181 and rs 1799793 gene polymorphism does not affect the sensitivity of the gastric cancer patients with chemotherapy.Chapter Ⅱ:ERCC1 and ERCC2 gene polymorphisms related to the prognosis of patients with advanced gastric cancer in oxaliplatin chemotherapy.Background and objective:Gastric cancer is one of the world’s fifth most common tumor,lung cancer in breast cancer incidence of prostate cancer after colorectal cancer and cervical cancer;Fatality rate in the fourth,in lung cancer after breast cancer of the liver.It is estimated that by 2012,a total of 2012 new patients with gastric cancer,accounting for 6.0%of all cancer is about 70%(677000 cases,including 456000 men and 221000 women)of gastric cancer occurs in the underdeveloped areas,about 50%of new cases of gastric cancer in China.According to the WHO’s international agency for research on cancer,according to the sequence of the gastric cancer in China,ranked second,2012 new cases for diagnosis of gastric cancer in China,404996 people,because of 325166 patients with gastric cancer death.Mechanisms of gastric cancer and other tumors,by a variety of environmental factors lead to the function and way of life,including helicobacter pylori infection Long-term drinking Eat too much of high salt diet Like eating pickled food and smoked food Eat fresh food Eat less and eating fresh vegetables and fruit,etc.In terms of genetic factors,previous studies have shown that cancer of the stomach have tendency of familial aggregation At the same time exposed to similar environmental factors and lifestyle risk factors for gastric cancer under the conditions of the individual,the onset of gastric cancer has great individual differences,not occur in all patients with cancer of the stomach,the reasons for this difference is mainly due to genetic factors.DNA repair mechanisms for stability and integrity of the human genome plays a very important role,the lack of these mechanisms may increase the occurrence of tumor susceptibility ERCC1 and ERCC2 is nucleotide excision repair ways of two important genes,ERCC1 and ERCC2 gene polymorphism may cause DNA damage and DNA adduct identification and shear nucleotide excision repair repair mechanism is damaged,transcription and base increase genome instability,leading to cancer susceptibility.The purpose of this part from molecular level to explore ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 rs1799793 and the relationship between gene polymorphism and susceptibility to gastric cancer,as well as the interaction between genes and environmental factors,so as to provide a scientific basis for comprehensive prevention and treatment of gastric cancer.Methods:Between March 2011-March 2013,gastric cancer patients were accepted in Inner Mongolia medical university affiliated people’s hospital pathology diagnosis 206 cases as group into in the hospital for a medical healthy individuals were 242 cases as control group adopts questionnaire group and control group in the social demographic characteristics life habit eating habits of the digestive system disease and family history.Included in the study before each object before using EDTA-Na2 anticoagulant tube pump case group and control group subjects venous blood 5 ml,put in-20 C refrigerator save standby ERCC1 rs 11615 and rs3212986 and ERCC2 rs13181 and rs 1799793 gene polymorphism detection using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)method.After reaction,the product will take 10 mu 1 used for preliminary analysis,placed on a 3%agarose gel electrophoresis and analysis system of spare specificity and the result is acceptable to save the rest of the preparation of the product of in-20 using SPSS 19.0(version 19.0,SPSS Inc.,Chicago,IL,USA),statistical analysis,all the statistical tests are bilateral inspection,and P value less than 0.05 was considered significant different.Results:Two groups by chi-square or t test to compare the general demographic characteristics of lifestyle and eating habits,found that the two groups in drinking or not(chi-square = 4.48,P = 4.48)to eat sour pickled cabbage or not(chi-square =14.46,P<14.46)like eating fresh vegetables or not(chi-square = 16.55,P<16.55)like eating hot food or not(chi-square = 5.43,P = 5.43),and family history of malignancy(chi-square = 15.93,P<0.001),the difference was statistically significant.The environmental impact factors are multiariable logistic regression analysis found that gender drinking Like eating sauerkraut Like eating fresh vegetables and family history of malignant tumor and the occurrence of gastric cancer risk correlation(P<0.05)in which gender(OR = 2.34,OR95%CI = 1.53 3.58)drinking(OR = 1.57,OR95%CI = 1.03 2.38)to eat sour pickled cabbage(OR = 2.77,OR95%CI=1.604.80)and malignant tumor family history(OR = 4.15,OR95%CI= 1.76 9.80)is a risk factor for gastric cancer,will increase the risk of suffering from cancer of the stomach;And like eating fresh vegetables(OR = 0.49,OR95%CI= 0.33 0.74)is the protective factors of gastric cancer,can reduce the risk.ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene frequency distribution were accord with Hardy-Weinberg genetic equilibrium.ERCC1 rs3212986 gene frequency in the case group and control group in allele frequency distribution difference was statistically significant(chi-square = 5.25,P ＝5.25)ERCC rs 1799793 gene frequency in the case group and the control group gene frequency distribution(chi-square = 10.81,P = 10.81)and allele frequency distribution(chi-square = 10.49,P = 10.49)no statistically significant difference.Multiariable logistic regression,after the adjustment of environmental confounders results showed that carry ERCC1 rs3212986 CA and AA genotype individuals and carry ERCC1 rs3212986 CC genotype compared to the individual,the individual risk of gastric cancer were increased 3.15 times(OR = 3.15,95%CI = 1.29 7.74)and 4.23(OR = 4.23,95%CI = 1.82 9.85)carry ERCC1 rs3212986 CA + AA genotype individuals and carry ERCC1 rs3212986 CC genotype individuals compared to a 1.70-fold increased risk of cancer of the stomach(OR = 1.70,95%CI = 1.11 2.62).And carry ERCC2 rs 1799793 AA genotype individuals compared to carry ERCC2 rs 1799793 AC and CC genotype individuals a 2.33-fold increased risk of cancer of the stomach(OR = 2.33,95%CI= 1.14 4.79)and 3.67(OR = 3.67,95%CI = 1.827.42)and carry ERCC2 rs 1799793 AC + CC genotype individuals and carry ERCC2 rs 1799793 AA genotype individuals compared to a 1.54-fold increased risk of cancer of the stomach(OR = 1.90,95%CI = 1.26 2.88).Multi-factor unconditioned logistic regression analysis found no ERCC1 rs11615 and ERCC2 rs13181 gene polymorphism could increase the risk of stomach cancer risk(P>0.05).Hierarchical analysis found that ERCC1 rs3212986 gene polymorphism and alcohol Like eating sauerkraut and family history of malignant tumor susceptibility to cancer of the stomach have interaction In addition,ERCC2 rs 1799793 gene polymorphism and alcohol Like eating fresh vegetables and family history of malignant tumors have interaction on gastric cancer susceptibility.ConcIusion:Hierarchical analysis found that ERCC1 rs3212986 gene polymorphism and alcohol Like eating sauerkraut and family history of malignant tumor susceptibility to cancer of the stomach have interaction In addition,ERCC2 rs 1799793 gene polymorphism and alcohol Like eating fresh vegetables and family history of malignant tumors have interaction on gastric cancer susceptibility.