Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility

AIM: To identify the association between methylenetetrahydrofolate reductase(MTHFR) polymorphisms and gastric cancer(GC) susceptibility.METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio(OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I2 statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed.RESULTS: Increased risk was found for the MTHFRC677T polymorphism under four genetic models(TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677 T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677 T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677 T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298 C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations(CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04). CONCLUSION: MTHFR C677 T polymorphism is a risk factor for GC, and the A1298 C polymorphism may be a protective factor against GC in eastern populations.

ERCC1 polymorphism, expression and clinical outcome of oxaliplatin-based adjuvant chemotherapy in gastric cancer

AIM: To determine the influence of excision repair cross complementing group 1 (ERCC1 ) codon 118 polymorphism and mRNA level on the clinical outcome of gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy. METHODS: Eighty-nine gastric cancer patients treated with oxalipatin-based adjuvant chemotherapy were included in this study. ERCC1 codon 118 C/T polymorphism was tested by polymerase chain reaction-ligation detection reaction (PCR-LDR) method in peripheral blood lymphocytes of those patients; and the intratumoral ERCC1 mRNA expression was measured using reverse transcription PCR in 62 patients whose tumor tissue specimens were available. RESULTS: No significant relationship was found between ERCC1 codon 118 polymorphism and ERCC1 mRNA level. The median relapse-free and overall survival period was 20.1 mo and 28.4 mo, respectively. The relapse-free and overall survivals in patients with low levels of ERCC1 mRNA were significantly longer than those in patients with high levels (P < 0.05), while there was no significant association found between ERCC1 118 genotypes and the disease prognosis. Multivariate analysis also showed that ERCC1 mRNA level was a potential predictor for relapse and survival in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy (P < 0.05). CONCLUSION: ERCC1 codon 118 polymorphism has no signifi cant impact on ERCC1 mRNA expression, and the intratumoral ERCC1 mRNA level but not codon 118 polymorphism may be a useful predictive parameter for the relapse and survival of gastric cancer patients receiving oxaliplatin-based adjuvant chemotherapy.

Polymorphisms of ERCC1, XPD, XRCC1 and XPG Predict Clinical Outcome in Advanced Gastric Cancer Patients Receiving Oxaliplatin-Based Chemotherapy in Chinese Population

OBJECTIVE To investigate whether polymorphisms in ERCC1,XPD,XPG,XRCC1 genes are associated with clinical outcomes inadvanced gastric cancer (AGC) patients treated with oxaliplatin-based chemotherapy.METHODS The genetic polymorphisms in ERCC1,XPD,XPG,XRCC1 were determined in 94 advanced gastric cancer patientstreated with oxaliplatin-based chemotherapy,using TaqMan-MGBprobes.The clinical response of 60 patients with stage Ⅳ disease,time to progression (TTP) and overall survival (OS) of 94 patientswere evaluated.RESULTS The overall disease control rate (CR + PR + SD) of the60 patients in stage Ⅳ was 70% (42/60).Patients with XRCC1 399G/G,XPG 46 C/C genotypes showed enhanced response to theoxaliplatin-based chemotherapy compared to those with othergenotypes (P<0.05).The median OS and TTP of the patientswere 5.5 months and 9.0 months,respectively.Among the 4types of polymorphisms in the study,XRCC1 399 G/A + A/A,XPG 46 C/T + T/T genotypes were regarded to be associatedwith chemoresistance and poor survival (P<0.05).Combinationanalysis of the 2 polymorphisms using the Kaplan-Meier methodrevealed that the TTP and OS of the patients with a number of riskgenotypes were significantly shortened (P<0.05).No significantassociation was found between the genotypes of the XPD codon751,the ERCC1 codon 118 and the clinical outcome (P>0.05).CONCLUSION Testing for XRCC1 399,XPG 46 polymorphismsmay allow identification of the gastric cancer patients whowill benefit from oxaliplatin-based chemotherapy.Specificpolymorphisms may influence clinical outcomes of AGCpatients.Selecting specific chemotherapy based on pretreatmentgenotyping represents an innovative strategy that warrantsprospective studies.

Folate levels in mucosal tissue but not methylenetetrahydrofolate reductase polymorphisms are associated with gastric carcinogenesis

AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation. METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls. Folate concentrations in these tissues were detected by the FOL ACS: 180 automated chemiluminescence system. MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP). RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16INK4A in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21WAF1 in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype. CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesisthrough hypomethylation and overexpression of c-myc.

X线修复交叉互补基因1多态性与进展期胃癌奥沙利铂联合卡培他滨方案化疗疗效的关系

目的:探讨X线修复交叉互补基因1(X-ray repair cross-complementing group 1,XRCC1) rs25487基因多态性与进展期胃癌奥沙利铂联合卡培他滨(XELOX方案)化疗的疗效及疾病进展时间的关系。方法:本研究为回顾性研究,入组110例进展期胃癌患者,均接受XELOX方案化疗,通过基质辅助激光解吸电离飞行时间质谱法的方法检测XRCC1 rs25487基因分型,分析患者临床病理特点及XRCC1 rs25487基因分型与患者化疗客观有效率(objective response rate, ORR)及疾病进展时间(progression-free survival, PFS)的关系。结果:110例进展期胃癌患者中,携带XRCC1 rs25487GG基因型、AG基因型、AA基因型分别为49例(44.5%)、52例(47.3%)、9例(8.2%),GG基因型患者ORR高于AG/AA基因型患者(53.1%vs 37.7%),但差异未达到统计学意义(χ^(2)=2.594,P=0.107)。GG基因型患者比AG/AA基因型患者PFS更长[6.3个月(95%CI:5.7~6.9)vs 5.0个月(95%CI:4.4~5.6),P=0.049]。患者临床病理特征均与化疗疗效无关,但肿瘤分化程度及TNM分期与PFS有关(P均<0.05)。Cox回归显示,肿瘤分化程度、TNM分期及XRCC1 rs25487是影响PFS的独立因素。结论:XRCC1 rs25487基因型与进展期胃癌患者XELOX方案化疗疗效密切相关,测定XRCC1 rs25487基因型可以为进展期胃癌的个体化治疗提供参考。

Polymorphism of methylenetetrahydrofolate reductase gene is associated with response to fluorouracil-based chemotherapy in Chinese patients with gastric cancer

Background The importance of polymorphisms in the methylenetetrahydrofolate reductase （MTHFR） gene for the prediction of the response to fluorouracil-based adjuvant chemotherapy in gastric cancer patients remains unclear. The aim of this study is to assess the predictive value of several polymorphisms of the MTHFR gene for clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. Methods Three hundred and sixty-two Chinese patients with gastric cancer were treated with fluorouracil-based adjuvant chemotherapy. DNA samples were isolated from peripheral blood collected before treatment. The three single nucleotide polymorphisms （SNPs） （rs1801131, rs1801133, rs2274976） genotypes of the MTHFR gene were determined by matrix- assisted laser desorption/ionization time-of-flight mass spectrometry （MALDI-TOF MS）. Results The average response rate for chemotherapy was 46.7%. Homozygous genotypes rs2274976G/G （X2=22.7, P 〈0.01） and rs1801131A/A （X2=14.3, P=0.008） were over-represented in responsive patients. Carriers of the rs2274976A allele genotypes （G/A and A/A） and of the rs1801131C allele genotypes （A/C and C/C）were prevalent in nonresponsive patients. In the haplotype association analysis, there was a significant difference in global haplotype distribution between the groups （X2=20.69, P=0.000 124）. Conclusions These results suggest that polymorphisms of the MTHFR gene may be used as predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of MTHFR gene as clinical markers for predicting the response to fluorouracil-based therapy in gastric cancer patients is warranted.

XRCC6基因多态性与术后化疗胃癌患者预后的关系

目的探讨X-射线修复交叉互补蛋白6(XRCC6)基因多态性与术后化疗胃癌患者预后的关系。方法选取99例术后行奥沙利铂+替吉奥化疗方案治疗的胃癌患者作为研究对象,检测其入院时外周血XRCC6基因rs2267437位点基因型。随访患者化疗36个月后的生存情况,将其分为存活组56例和死亡组43例。比较两组患者的临床病理资料和XRCC6基因基因型的分布频率,并采用COX回归模型分析XRCC6基因多态性与术后化疗胃癌患者预后的关系。结果死亡组肿瘤直径>5 cm、肿瘤临床分期为Ⅲ期、发生淋巴结转移、存在远处转移的患者比例更高(均P<0.05)。两组患者的XRCC6基因的基因型分布频率差异有统计学意义(P<0.05),其中死亡组患者的XRCC6基因CG基因型、GG基因型频率低于存活组。COX回归分析结果显示,校正相关临床病理特征后,携带XRCC6基因CG/GG基因型的术后化疗胃癌患者的预后更好(P<0.05)。结论XRCC6基因多态性与术后化疗的胃癌患者的预后密切相关,携带CG/GG基因型的患者预后更好。

亚甲基四氢叶酸还原酶基因C677T多态性与胃癌患者对5-FU化疗敏感性的关系

背景和目的亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase,MTHFR)基因变异影响MTHFR的活性,以致影响体内5,10-MTHF的浓度,从而影响5-FU的抗瘤活性。本研究旨在观察MTHFR基因C677T多态性对预测胃癌患者对5-FU的敏感性和化疗毒性的影响。方法收集经病理学确诊的晚期胃癌75例。所有病例化疗前抽外周静脉血2ml,用PCR-RFLP技术检测研究对象的MTHFR基因型。基因型分为野生型纯合子(C/C)、杂合子(C/T)、变异型纯合子(T/T)3种类型。所有患者经含5-FU为基础的联合化疗方案化疗。结果75例晚期胃癌患者中,MTHFRC/C基因型24例(32.0%),MTHFRC/T基因型33例(44.0%),MTHFRT/T基因型18例(24.0%)。其中22例PR,29例NC,24例PD,化疗总有效率29.3%。MTHFRT/T基因型患者的化疗有效率(20/24,83.3%)明显高于MTHFRC/C基因型患者(2/24,8.3%)(χ2=24.01,P<0.001),同样高于MTHFRC/T基因型患者(5/33,15.2%)(χ2=22.7,P<0.001)。MTHFRC/C基因型患者的化疗有效率与MTHFRC/T基因型患者之间无显著性差异(χ2=0.6,P=0.439)。非条件多元Logistic回归分析(调整性别、年龄、化疗方案、辅助化疗因素的影响)结果显示C/C+C/T基因型患者对化疗有效的可能性为T/T基因型患者的0.017倍(95%CI0.003～0.102,P<0.001)。

ERCC1 mRNA表达及基因多态性对胃癌辅助化疗预后的影响

目的:探讨切除修复交叉互补基因(ERCC1)mRNA表达及118C/T基因多态性与胃癌对奥沙利铂辅助化疗预后的关系。方法:根治术后胃癌患者62例,采用奥沙利铂为主的方案进行辅助化疗。采用半定量RT-PCR方法检测胃癌组织中ERCC1 mRNA水平。采用PCR-LDR(连接酶检测反应)检测ERCC1118C/T基因多态。结果:62例胃癌组织ERCC1 mRNA表达水平的中位值为0.672;ERCC1118C/C、C/T和T/T基因型分别占51.6%(32/66)、43.5%(27/62)和4.8%(3/62)。ERCC1 mRNA高表达组(>0.672)无复发生存率和总生存率均显著低于低表达组(P<0.05);携带C/T和T/T基因型患者与C/C基因型患者的无复发生存率和总生存率差异无显著性(P>0.05)。多因素分析结果显示ERCC1 mRNA水平是影响患者预后的独立危险因素(P<0.05),而ERCC1118C/T多态与预后无关(P>0.05)。结论:ERCC1 mRNA表达水平与接受奥沙利铂为主辅助化疗胃癌患者的预后有关,可用于其预后预测。

XRCC1基因多态性对晚期胃癌患者化疗疗效及生存期的影响

目的:考察X射线损伤修复交叉互补基因1(XRCC1)Arg399Gln(G→A)多态性对晚期胃癌患者奥沙利铂+氟尿嘧啶化疗疗效及生存期的影响。方法:选取2013年1月-2015年1月海南省人民医院晚期胃癌患者52例,予奥沙利铂+氟尿嘧啶联合化疗,每3周为1个周期,均治疗3个周期以上。采用聚合酶链反应-连接酶检测反应法测定患者的基因型,比较不同基因型患者的疾病控制率和无进展生存期。结果:52例晚期胃癌患者中,XRCC1 GG基因型28例(53.8%)、GA基因型21例(40.4%)、AA基因型3例(5.8%),各基因型频率均符合Hardy-Weinberg平衡(P>0.05)。52例患者的疾病控制率为76.9%,其中GG基因型患者的疾病控制率(92.9%)显著高于GA+AA基因型(58.3%),差异有统计学意义(P<0.05);52例患者的平均无进展生存期为(7.1±1.2)个月,其中GG基因型患者的无进展生存期[(8.6±0.8)个月]显著长于GG+GA基因型[(5.9±0.7)个月],差异有统计学意义(P<0.05)。结论:XRCC1多态性与晚期胃癌患者奥沙利铂+氟尿嘧啶化疗疗效及无进展生存期有关,且XRCC1 GG基因型患者对化疗药物更敏感;该基因可能成为该类方案化疗疗效及生存期的预测标志物。

胃癌铂类化疗预后与XRCC1多态性关系

目的探讨外周血X线交错互补修复基因1(XRCC1)单核苷酸多态性与接受铂类药物化疗胃癌患者生存时间关系。方法经病理确诊胃癌患者62例,治疗前提取其外周血DNA,采用TaqMan探针Real-time PCR方法对XRCC1第399位密码子进行多态性分析,并比较其基因型与接受铂类化疗患者生存时间关系。结果62例胃癌患者平均总生存时间为461 d,携带XRCC1 Arg/Arg或Arg/Gln基因型胃癌患者的平均总生存时间为490 d,而携带Gln/Gln基因型患者的平均总生存时间仅为295 d,差异有统计学意义(P=0.022)。结论XRCC1基因多态性与接受铂类化疗的胃癌患者的总生存时间明显相关。

亚甲基四氢叶酸还原酶基因多态与胃癌易感性

目的探讨福建省人群亚甲基四氢叶酸还原酶(MTHFR)C667T基因多态与贲门癌、非贲门部胃癌易感性关系,及其与叶酸摄入和饮酒的交互作用。方法采用共同对照的病例对照研究方法,聚合酶链反应限制性片段长度多态性(PCRRFLP)方法检测基因型。结果多因素分析结果显示,MTHFR变异基因型(CT或TT)增加非贲门部胃癌发生的危险。变异基因型与新鲜蔬菜、水果摄入少和常饮酒在贲门癌发生中存在交互作用,与豆制品和新鲜水果低摄入在非贲门部胃癌发生中存在交互作用。结论MTHFR变异基因型与低叶酸和常饮酒协同增加贲门癌发生的危险,变异基因型是非贲门部胃癌的危险因素,与低叶酸摄入协同增加非贲门部胃癌的危险。贲门癌与非贲门部胃癌的危险因素不尽相同。

亚甲基四氢叶酸还原酶A1298C多态性与胃癌易感性的关系

[目的]探讨亚甲基四氢叶酸还原酶（MTHFR）基因多态性与胃癌易感性的关系及与环境因素的交互作用。[方法]收集南京市原发性胃癌患者169例，采用1：1病例．对照研究方法随机选取非消化系统疾病、非肿瘤病人为对照，进行流行病学调查，取外周血，采用限制性片段长度多态性方法（PCR—RFLP）分析研究对象MTHFR1298位点的多态性，并分析MTHFR1298基因多态性与烟酒嗜好在胃癌发生中的交互作用。[结果]MTHFRl298C等位基因在病例组与对照组中的频率分别为21．6％和13．0％，差异具有显著性（x^2=8．693，P=0．003，OR=1．841，95％CI=1．223—2．772）。携带MTHFR1298A／C基因型者患胃癌危险性增高（x^2=10．994，P=0．001，OR=2．160，95％CI=1．365—3．419），携带A／C基因型同时又吸烟者患胃癌的危险性是AM型不吸烟者的3．289倍（x^2=10．002，P=0．002，95％CI=1．573～6．880），携带A／C基因型不饮酒者患胃癌的危险性是携带A／A基因型不饮酒者的2．726倍（x^2=12．459，P〈0．001，95％CI=1．562—4．758），同时携带A／C基因型、吸烟、饮酒者患胃癌的危险性是携带A／A基因型、不吸烟、不饮酒者的2．394倍（x^2=3．933，P=0．047，95％CI=1．010—5．672）。[结论]MTHFR1298A/C基因型可增加胃癌易感性，并与吸烟、饮酒间存在交互作用。

胃癌亚甲基四氢叶酸还原酶基因1298AC多态性与H.pylori感染的关系

目的 探讨重庆地区胃癌人群亚甲基四氢叶酸还原酶 (MTHFR)基因 12 98AC多态性及与H .pylori感染的关系。方法 采用聚合酶链反应和限制性片段长度多态性 (PCR RFLP)技术 ,检测 12 2例胃癌和 10 1例正常对照的MTHFR基因 12 98AC多态性 :采用PCR和Warthin Starry银染色法检测幽门螺杆菌 (H .pylori)。结果 胃癌组 12 98AA、12 98AC和12 98CC 3种基因型频率分别为 5 9.8%、3 6.1%和 4.1% ,与对照组中 3种基因型频率 5 7.4%、3 7.6%和 5 .0 %相比无显著差异 (P >0 0 5 )。以 12 98AA基因型的OR为 1.0 0 ,胃窦癌AC基因型的OR为 0 .87( 95 %CI,0 .42～ 1.82 ) ,CC基因型的OR为0 .41( 95 %CI ,0 .0 5～ 3 .72 )。胃癌MTHFR 12 98AC 3种基因型中H .pylori的检出率无明显差别 (P >0 0 5 )。结论 重庆地区人群中MTHFR 12 98AC多态性可能是胃窦癌的保护因素 ,MTHFR 12 98AC多态性与H .pylori感染无关。

RRM1单核苷酸多态性与非小细胞肺癌患者对吉西他滨化疗敏感性的相关性研究

目的:探讨核苷酸还原酶M1亚基(RRM1)的单核苷酸多态性(SNPs)与非小细胞肺癌(NSCLC)患者对吉西他滨化疗敏感性的相关性。方法:选取2014年8月-2016年7月我院NSCLC初治患者96例,均接受以吉西他滨为基础的两药联合化疗方案,连续化疗至少2个周期(每28 d为1个周期)。以完全缓解、部分缓解的患者总数与受试患者总数的比值来计算化疗敏感率;采用聚合酶链反应和直接测序法检测其RRM1基因型;分析患者不同基因型与化疗敏感性的相关性。结果:RRM1-37C>A的CC、CA、AA基因型分布频率分别为35.42%、52.08%、12.50%,-524C>T的CC、CT、TT基因型分布频率分别为18.75%、37.50%、43.75%,各基因型分布频率均符合Hardy-Weinberg平衡(P>0.05)。96例NSCLC患者的化疗敏感率为37.50%。患者的年龄、性别、民族、吸烟与否、TNM分期、病理类型、化疗方案和美国东部肿瘤协作组评分与化疗敏感性无关(P>0.05)。RRM1(-37CA)+(-524CT)、(-37CC)+(-524TT)基因型患者的化疗敏感率(57.14%、39.39%)均显著高于其他基因型患者(10.71%),差异均有统计学意义(P<0.05);而RRM1(-37CA)+(-524CT)与(-37CC)+(-524TT)基因型患者的化疗敏感率比较,差异无统计学意义(P>0.05)。结论:NSCLC患者RRM1的SNPs可作为评价吉西他滨化疗敏感性的预测因子,RRM1(-37CA)+(-524CT)和(-37CC)+(-524TT)基因型患者对该类化疗方案具有更高的敏感性。

XRCC1基因多态与晚期胃癌化疗敏感性的关系

目的观察DNA修复酶XRCC1基因密码子399和194多态与晚期胃癌患者对5-氟尿嘧啶(5-FU)和铂类药物化敏感性的关系。方法 91例晚期胃癌患者给予5-FU和铂类药物方案治疗,化疗前检测XRCC1基因型。观察化疗疗效及其与XRCC1基因多态性的关系。结果本组化疗有效率为37.4%。XRCC1399和XRCC11943种基因型化疗有效率比较差异均无统计学意义(P>0.05)。XRCC1399杂合子Arg/Gln基因型骨髓抑制发生率为25.7%低于纯合子基因型(Gln/Gln和Arg/Arg)的50.0%和47.8%;XRCC1399Gln等位基因携带型(Gln/Gln和Arg/Gln)呕吐反应发生率为30.0%和31.4%低于Arg/Arg基因型的54.4%;XRCC1194Trp/Trp基因型骨髓抑制发生率为0低于Arg等位基因携带型(Arg/Trp和Arg/Arg)的41.5%和45.2%,差异均有统计学意义(P<0.05)。结论 XRCC1基因多态性与晚期胃癌患者对5-FU为基础的含铂类药物方案化疗疗效的关系不确切,但与晚期胃癌对5-FU和铂类药物化疗的Ⅱ度以上严重不良反应发生有关,检测XRCC1基因型可以为晚期胃癌化疗药物的选择、避免严重毒副反应的发生提供参考依据。

亚甲基四氢叶酸还原酶基因C677T多态性与肺腺癌化疗疗效的关系

目的观察肺腺癌患者亚甲基四氢叶酸还原酶(MTHFR)基因C677T多态性与化疗疗效的关系。方法化疗前抽取92例肺腺癌患者外周血液,用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)方法检测MTHFR基因C677T多态性,并分析其与化疗的疗效关系。结果 92例肺腺癌患者中,MTHFR基因C677T野生型(CC)的分布为60.9%(56/92),纯合突变型(TT)为14.1%(13/92),杂合突变型(CT)为25.0%(23/92)。一线化疗方案使用培美曲塞/卡铂的疗效:野生型(CC)PR 20例,SD 19例,PD 17例,总有效率(ORR)为35.7%;纯合突变型(TT)PR 2例,SD 7例,PD 4例,ORR为15.4%;杂合突变型(CT)SD 13例,PD 10例,ORR为0。CC型患者化疗ORR显著高于TT型和CT型者(P=0.001)。CC型与TT型/CT型患者的肿瘤进展时间(TTP)分别为6.2个月和4.7个月,差异有统计学意义(P=0.023)。二线化疗方案使用吉西他滨/奈达铂或多西紫杉醇/奈达铂的疗效:CC型PR 2例,SD 5例,PD 10例;TT型SD 3例;CT型PR 1例,SD 2例,PD 7例,CC型与TT型/CT型患者的ORR比较,差异无统计学意义(P=1.000)。结论 MTHFR基因C677T野生型(CC)肺腺癌患者可能是使用培美曲塞联合卡铂化疗有效的人群。MTHFR基因C677T CC型患者的TTP显著长于TT型患者和CT型患者。MTHFR基因C677T多态性与吉西他滨/奈达铂或多西紫杉醇/奈达铂化疗疗效无关。

胃癌组织中肿瘤相关基因甲基化及其表达与叶酸和代谢酶MTHFR基因多态性的关系

目的:探讨人胃癌组织中癌基c-myc,抑癌基因p16INK4A,p21WAF1,错配修复基NhMLH1和hM2SH2的甲基化状态及其表达与叶酸、MTHFR基因多态性的关系．方法:胃癌38例手术切除标本的癌区、癌旁和外周正常黏膜组织,运用FOL ACS:180自动化学发光系统测定叶酸含量,PCR-RFLP技术检测MTHFR基因677(C→T)和1298(A→C)两个常见多态,并分别以Real—time RT-PCR和甲基化特异性PCR (MSP)技术检测肿瘤相关基因的表达和甲基化状态．结果:c-myc表达升高,p16INK4A,hMLH1和hMSH2表达降低的胃癌黏膜组织其基因启动子区异常甲基化．p21WAF1,hMSH2表达降低, p16INK4A高甲基化者叶酸水平明显降低,c-myc低甲基化和表达升高者中均存在低叶酸水平．MTHFR 677CC基因型的胃癌黏膜组织p16INK4A甲基化升高且表达降低,而其余肿瘤相关基因的甲基化及其表达与MTHFR两个常见多态均无明显相关性．结论:DNA甲基化在胃癌的发生、发展中具有重要作用,叶酸水平和MTHFR基因多态性通过影响部分肿瘤相关基因的甲基化状态而调控其表达．

DNA修复基因多态性影响晚期胃癌卡培他滨联合奥沙利铂化疗的临床预后

目的:探讨DNA修复基因(ERCC1、ERCC2、XRCC1)单核苷酸多态性对胃癌患者卡培他滨联合奥沙利铂化疗敏感性的相关性。方法:本回顾性研究选取XELOX作为一线化疗方案的100例晚期胃癌患者为研究对象,检测分析三个基因六个单核苷酸多态性位点(ERCC1 rs11615;ERCC2 rs13181,rs1799793;XRCC1rs25487,rs25489,rs1799782),同时分析其与临床预后的关系。结果:XRCC1 rs25487的A/G等位基因频率、AG/AA/GG基因分布频率均与疾病化疗敏感性和无进展生存期有关,携带GG基因型患者疗效好(P<0.05),中位PFS为8.00个月(95%CI:6.34~9.66);ERCC2 rs13181的G/T等位基因频率、GG/GT/TT基因分布频率与疾病化疗敏感性和无进展生存期明显相关,携带TT基因型患者疗效好(P<0.05),中位PFS为7.46个月(95%CI:6.45~8.48)。COX比例风险模型显示ERCC2 rs13181 G/T基因型是晚期胃癌无进展生存期的独立风险因素之一(HR=0.72,95%CI:0.53~0.97,P=0.025)。结论:ERCC2 rs13181基因多态性可能是评估接受XELOX化疗晚期胃癌患者预后的关键指标。

亚甲基四氢叶酸还原酶基因多态性与胃癌关系的研究

目的 探讨重庆地区人群亚甲基四氢叶酸还原酶基因多态性与胃癌的关系。方法 采用聚合酶链反应和限制性片段长度多态性技术 ,检测 6 6例胃癌和 10 1例正常对照的MTHFR基因C6 77T多态性。结果 MTHFRC6 77T呈多态性 ,可分为3种类型 :6 77CC、6 77CT、6 77TT。胃癌组 3种基因型频率分别为 :6 77CC 4 5 .5 %、6 77CT 4 0 .9%、6 77TT 13.6 % ,等位基因频率6 77C为 6 5 .9% ,6 77T为 34.1%。对照组中 6 77基因频率分别为 :6 77CC 4 8.5 %、6 77CT 4 2 .6 %、6 77TT 8.9% ,等位基因频率6 77C为 6 8.8% ,6 77T为 31.2 % ,胃癌组与对照组相比无显著差异。以 6 77CC基因型作为参考 ,胃贲门癌 6 77CT基因型OR为0 .2 1,95 %CI(0 .0 3～ 0 .99) ,6 77CT +TT基因型OR为 0 .2 6 ,95 %CI(0 .0 7～ 0 .98) ;胃体癌 6 77TT基因型OR为 3.6 3,95 %CI(1.0 2～ 12 .72 )。结论 重庆地区人群中 ,亚甲基四氢叶酸还原酶基因C6 77T多态性是胃贲门癌的保护因素 。