胃癌组织中胸苷酸合成酶、胸苷磷酸化酶mRNA表达及其临床意义

背景与目的:化学治疗在胃癌治疗中扮演了重要的作用。通过肿瘤组织中某些基因表达的水平来选择化疗药物已成为今后化疗的方向。胸苷酸合成酶(TS)、胸苷磷酸化酶(TP)是氟尿嘧啶(5-FU)体内的关键代谢酶,其表达水平影响恶性肿瘤患者接受5-FU化疗后的预后。本研究探讨胃癌组织中TS、TP mRNA表达水平与预后的关系。方法:采用实时定量RT-PCR技术检测51例胃腺癌组织TS、TP mRNA表达水平。结果:胃癌组织TS、TP mRNA表达水平的中位数分别为0.94和21.20,TS高表达组和低表达组之间无瘤生存期和总生存期差异有显著性(P<0.05),TP高表达组和低表达组之间总生存期差异有显著性(P<0.05),但无瘤生存期之间差异无显著性(P>0.05)。TS、TP mRNA表达与年龄、性别、淋巴结转移、组织学分级及临床分期均无相关性(P>0.05)。结论:检测TS、TP mRNA表达水平对接受5-FU为基础治疗方案的胃癌患者的预后有很好的预测价值。     

胸苷酸合成酶的表达及其与胃癌的相关性

目的 探讨胃癌组织中胸苷酸合成酶(TS)的表达及其与临床病理因素的关系.方法 采用免疫组织化学染色的方法(S-P法)检测了48例胃癌组织中TS基因表达情况,并用SPSS10.0统计软件分析其与临床病理因素的关系.结果 48例胃癌组织中TS基因表达的阳性率为52.1%(25/48); TS的表达与肿瘤分化程度、浸润深度、淋巴结转移与否及临床病理分期密切相关(P<0.05).结论 胃癌组织中TS表达水平可能是胃癌患者1个重要的预后指标.     

结直肠癌组织胸苷酸合成酶的表达及临床意义

目的:探讨了胸苷酸合成酶(TS)在结直肠癌组织中的表达及其与临床病理特征和预后的关系。方法:用免疫组化SP法检测72例结直肠癌组织中TS的表达,按TS表达水平将患者分为2组:高表达组和低表达组,用Kaplan-Meier法分析TS的表达与临床病理特征和预后的相关性。用多因素COX模型分析影响患者预后的相关因素。结果:在72例结直肠癌组织中TS表达从15%~95%不等,平均(49.79±25.05)%。TS的表达随Dukes分期的增加而增加,但无统计学意义(P=0.145)。早期(Dukes A~B)结直肠癌的预后明显优于晚期结直肠癌(Dukes C、D),P<0.0001。TS低表达者预后优于高表达患者。治疗前血清CEA、CA19-9水平正常者预后较好,CEA、CA19-9升高者预后较差。多因素分析显示Dukes分期、TS表达状况、CEA是影响预后的因素。结论:结直肠癌治疗前Dukes分期是影响预后的主要因素。TS的表达状况、CEA也是影响预后的参考指标。     

Rb磁物表达与胃癌预后的关系

Ｒｂ基因是细胞生长分化的重要调控因子，我们应用Ｓ－Ｐ免疫组织化学方法研究Ｒｂ基因产物表达与胃癌临床病理学特点和预后的关系。本组胃癌Ｒｂ基因产物阳性表达为６２／８５，与淋巴结呈极显著性相关，与胃癌术后生存期呈极显著性负相关。     

胃癌组织中VEGF、CD105表达与预后的关系

目的:探讨VEGF、CD105在胃癌组织中的表达及临床意义.方法:采用免疫组织化学法检测53例胃癌组织中VEGF、CD105表达,探讨其与临床病理特征及预后之间的关系.结果: 胃癌组织中VEGF的表达率是60.5%,VEGF的表达与临床分期、淋巴结转移有关,与性别、年龄、肿瘤分化程度无关.VEGF阳性表达的病人总生存率比阴性表达者低.结论: VEGF表达水平异常增高在胃癌的发生发展过程中起重要作用,检测VEGF、CD105表达水平可判断胃癌病人预后及为术后辅助治疗提供参考依据.     

人端粒酶逆转录酶mRNA在胃癌组织中的定量表达及其与胃癌预后的关系

目的 探讨人端粒酶逆转录酶(hTERT)mRNA在胃癌组织中的表达,及其与胃癌生物学行为和根治术后患者预后的关系.方法 应用荧光定量逆转录聚合酶链反应(RT-PCR)检测89例胃癌根治性切除术后患者的肿瘤组织和阴性切缘组织中hTERT mRNA的表达量,对hTERT mRNA表达量与患者的临床病理参数(年龄、性别、肿瘤大小、肿瘤部位、病理类型、组织分化程度、浸润深度、淋巴结转移情况、pTNM分期及生存期)进行单因素分析,采用Cox模型进行胃癌患者生存的多因素分析.结果 hTERT mRNA在阴性切缘组织中的表达量为11.37±2.15,在胃癌组织中的表达量为16.98±3.56,差异有统计学意义(P<0.05).胃癌组织中hTERT mRNA的表达量与组织学分级、浸润深度、pTNM分期及淋巴结转移呈正相关(P<0.05),与胃癌患者的生存期呈负相关(P<0.01).结论 胃癌组织中hTERT mRNA高表达表明胃癌恶性程度较高且病期较晚,检测胃癌组织中hTERTmRNA的表达水平有助于对胃癌患者的预后做出更准确的判断.胃癌组织中hTERT mRNA的表达量、肿瘤浸润深度和pTNM分期是影响胃癌患者预后的重要因素.

Abstract：

Objective By quantitative detection of telomerase expression, we investigated the relationship between telomerase expression and malignant behavior and prognosis in gastric carcinoma.Methods A real-time quantitative RT-PCR (RQ-PCR) was used to quantify the hTERT mRNA copy numbers in 89 samples of gastric carcinoma and corresponding non-cancerous tissues.The clinicopathological data of enrolled patients such as age, sex, tumor size, tumor site, pathologic type, histodifferentiation,infiltration depth, lymph node metastasis, stage and survival were obtained, and were made one factor analysis of variance and COX regression prognostic analysis with those above mentioned markers.Follow-up was completed as of February 28, 2010.The median follow-up was 24 months.Results hTERT from gastric carcinomas and corresponding non-cancerous tissues was 16.98 ± 3.56 and 11.37 ± 2.15, respectively (P<0.05 ),the telomerase activity in gastric cancer was significantly higher than that in non-cancerous tissue ( P < O.05 ).Telomerase activity showed a positive correlation with depth of invasion, tumor differentiation and nodal metastasis ( P < 0.01 ), and negative correlation with survival.Conclusions Gastric cancer with high hTERT mRNA expression indicates a more malignant potential.Detection of hTERT mRNA in gastric cancer may be useful in a better understanding of invasion, metastasis, as well as prognosis of gastric cancer and provide a more efficient therapy.The quantitative expression of hTERT mRNA, infiltration depth and pTNM stage are significant afactors affecting the prognosis of patients with gastric carcinoma.     

乳腺癌组织中TP和TS及DPD mRNA表达与预后的关系

目的　探讨乳腺癌组织中胸苷酸化酶 (TP)、胸苷酸合成酶 (TS)和二氢嘧啶脱氢酶(DPD)mRNA表达水平及其与预后的关系。方法　采用real time定量PCR技术检测经过微选的 9例正常乳腺组织和 86例乳腺癌组织TP、TS和DPD的mRNA表达水平。结果　肿瘤组织中TP、TS和DPDmRNA表达水平中位数分别为 16 .5 4 ,0 .38和 2 .74 ,正常乳腺组织分别为 11.75 ,0 .2 5和 8.33,差异均无显著性 (P >0 .0 5 )。除年龄与DPD表达呈负相关外 ,TP、TS和DPDmRNA表达与肿瘤体积、淋巴结转移、组织学分级、临床分期均无相关性。TP、DPD高表达组和低表达组之间 ,无瘤生存期和总生存期差异均无显著性。TS高表达组和低表达组无瘤生存期差异无显著性 (P =0 .0 6 9) ;平均总生存期分别为 5 9.0 0和 70 .30个月 ,差异有显著性 (P =0 .0 4 96 )。结论　仅检测TSmRNA对判断乳腺癌预后有参考价值 ,同时检测TP、TS和DPD具有更好的预测价值。     

Rb基因产物表达与胃癌预后的关系

Rb基因是细胞生长分化的重要调控因子。我们应用S－P免疫组织化学方法研究Rb基因产物表达与胃癌临床病理学特声、和预后的关系。本组胃癌Rb基因产物阳性表达为62／85（72．94％），与淋巴结转移呈极显著性正相关（P＜0．01），与胃癌术后生存期呈极显著性负相关（P＜0．01）。Rb基因产物阳性级别高者，易发生淋巴结转移，生存期可能较短。检测Rb基因产物表达有助于胃癌生极学行为的认识及预后判断。     

胃癌组织中VEGF、CD105表达与预后的关系

目的：探讨VEGF、CD105在胃癌组织中的表达及临床意义。方法：采用免疫组织化学法检测53例胃癌组织中VEGF、CD105表达,探讨其与临床病理特征及预后之间的关系。结果：胃癌组织中VEGF的表达率是60．5％,VEGF的表达与临床分期、淋巴结转移有关,与性别、年龄、肿瘤分化程度无关。VEGF阳性表达的病人总生存率比阴性表达者低。结论：VEGF表达水平异常增高在胃癌的发生发展过程中起重要作用,检测VEGF、CD105表达水平可判断胃癌病人预后及为术后辅助治疗提供参考依据。     

转录因子Sp1在胃癌组织中的表达及其与胃癌预后的关系

目的探讨转录因子sp1在胃癌组织中的表达情况及与胃癌患者预后的关系。方法采用免疫组化方法,检测sp1在86例胃癌组织、53例淋巴结转移灶和57例正常胃黏膜组织中的表达情况,利用凝胶电泳迁移率分析(EMSA)检测正常胃黏膜组织和胃癌组织中的sp1活性。应用Cox比例风险回归模型进行多因素分析,确立影响预后的独立因素。结果Sp1蛋白主要在黏液颈细胞胞核内表达,在胃小凹和腺上皮细胞中未见表达。同时,SP1在胃癌组织中高表达,而在胃癌邻近组织、胃癌间质细胞和腺体细胞中呈弱表达或无表达。在胃癌组织中,Sp1阴性表达、弱表达和高表达患者的中位生存时间分别为43个月、47个月和8个月,生存率差异有统计学意义(P<0.01)。多因素分析显示,Sp1表达、肿瘤分期是影响患者预后的独立因素。结论Sp1在胃癌组织中高表达,可作为预测胃癌患者预后的重要指标。     

Association of thymidylate synthase polymorphisms with gastric cancer susceptibility

We investigated in a case-control study a possible role of thymidylate synthase gene (TS) polymorphisms for gastric cancer susceptibility. Lymphocyte genomic DNA from 134 Italian gastric cancer patients and 139 controls was used for genotyping two polymorphisms in the TS 5'-untranslated region (5'-UTR); a double (2R) or triple (3R) 28-bp repeat and a G/C polymorphism within the triple repeats allele (3G allele). Samples were also genotyped at a 6-bp deletion/insertion (del6 or ins6) polymorphism at position 1494 in the TS 3'-untranslated region (3'-UTR). Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with the disease. The global allelic distribution was in Hardy-Weinberg equilibrium. Genotypes with the 3G allele (2R/3G, 3C/3G, 3G/3G) were significantly more frequent in patients than controls and were associated with gastric cancer risk (OR = 2.06; 95% CI = 1.26-3.35). A significant risk was also observed for carriers of the del6 allele in the 3'-UTR. Odds ratios for combined 3G-del6/ins6 and 3G-del6/del6 genotypes were 2.59 (95% CI = 1.36-4.94) and 2.81 (95% CI = 1.22-6.64), respectively. The 3G-del6 haplotype showed a significant association with the disease (p = 0.01). Polymorphisms in the TS gene may contribute to gastric cancer susceptibility and this finding deserve further investigation in the context of novel strategies for gastric cancer prevention. In vitro, 3G genotypes have been related to high TS mRNA expression, which may underlie one of the possible etiologic mechanisms.     

Predictive value of thymidylate synthase expression in gastric cancer: a systematic review with meta-analysis

Purpose: The relationship between thymidylate synthase (TS) expression and outcomes in gastric cancer(GC) patients remains controversial, although most studies reported poor survival and reduced response tofluoropyrimidine were related to high TS in tumors. We carried out a systematic review of the literature withmeta-analysis to estimate the predictive value of TS expression from published studies. Methods: We indentified24 studies analysing the outcome data in gastric cancer stratified by TS expression. Effect measures of outcomewere hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS), or the odds ratio (OR) foroverall response rate (ORR). HRs and ORs from these eligible studies were pooled using random-effects metaanalysis.Results: Fifteen studies investigated outcomes in a total of 844 patients with advanced GC, and ninestudies investigated outcomes in a total of 1,235 patients with localized GC undergoing adjuvant therapy. Metaanalysisof estimates showed high TS expression was significantly associated with poor OS in the advanced setting(HR: 1.43, 95%CI: 1.08 - 1.90), and poor EFS in the adjuvant setting (HR: 1.53, 95%CI: 1.01 - 2.32). Subgroupanalysis demonstrated TS expression to haves even greater value in predicting OS, EFS and ORR in advancedGC patients treated with fluoropyrimidine monotherapy (HR for OS: 2.32, 95%CI: 1.53 - 3.50; HR for EFS:1.76, 95%CI: 1.19 - 2.60; OR for ORR: 0.32, 95%CI: 0.11 - 0.95). Conclusion: High levels of TS expression wereasssociated with a poorer OS for advanced GC patients compared with low levels. In the adjuvant setting, highTS expression was also associated with a worse EFS. Additional studies with consistent methodology are neededto define the precise predictive value of TS.     

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (> or = 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren's classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs. 57.2%, P = 0.548) and overall survival (59.6% vs. 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary.     

Expression of thymidylate synthase and thymidine phosphorylase in recurrence and survival rates of advanced gastric cancer

Background. The immunohistochemical expression of thymidylate synthase (TS) and thymidine phosphorylase (TP) was examined in a comparative study of the recurrence rates and prognoses of patients with advanced gastric cancer at the same stage. Methods. We examined the resected specimens of 67 patients with stage IIIB gastric cancer (pT3, pN2, M0) under 70 years of age who had undergone curative gastrectomy followed by adjuvant chemotherapy with 5-fluoropyrimidines. Paraffin sections of the resected specimens were stained with human anti-TS polyclonal and anti-TP monoclonal antibodies by the avidin-biotin-peroxidase complex (ABC) method. Results. The overall expression of TS and TP was 45.4% and 43.4%, respectively. The postoperative survival curve for the TS-positive group was significantly depressed compared with that for the TS-negative group ( P = 0.0480). The survival curves for TP-positive and TP-negative groups did not show any difference. In regard to the combination of TS and TP expression, the best survival curve was obtained for the TS(−)/TP(+) group, followed by those for the TS(−)/TP(−), TS(+)/TP(−), and TS(+)/TP(+) groups in descending order. With regard to the recurrence site, there was no significant difference in peritoneal recurrence in relation to positivity for TS or TP. Lymph node recurrence, however, was significantly higher in the TS-positive and TP-positive groups, with P -values being 0.0466 and 0.0058, respectively, versus the corresponding negative groups. The incidence of hepatic recurrence was higher in the TP-positive group than in the TP-negative group ( P = 0.0910). As for the total doses of 5-fluoropyrimidines given, more favorable survival curves were obtained for the high dose of negative TS and TP groups, but no significant differences were observed in their positivities. Conclusion. The expressions of TS and TP showed different characteristics in overall survival and recurrence rate or site. They should be used for predicting prognosis in comprehension on their properties. Received for publication on Dec. 21, 1998; accepted on Sept. 1, 1999     

Expression of multidrug resistance-associated protein1,P-glycoprotein,and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.     

TS和MMR联合检测在结直肠癌预后判断中的作用

目的:对133例结直肠癌患者临床病例资料进行回顾性分析,分析胸苷酸合成酶(thymidylate synthase,TS)蛋白与错配修复(mismatch repair,MMR)状态联合检测与结直肠癌患者临床病理特征及预后之间的关系.方法:免疫组化测定TS和MMR(MLH-1/MSH-2)蛋白表达.根据TS蛋白和MMR状态差异进行相应的配对组合,将纳入患者分为四组:TS蛋白高表达/MMR蛋白高表达(HtHm)组、TS蛋白低表达/MMR蛋白高表达(LtHm)组、TS蛋白低表达/MMR蛋白低表达(LtLm)组、TS蛋白高表达/MMR蛋白低表达(HtLm)组.分析TS和MMR联合检测与患者临床病理因素及预后的关系.结果:TS和MMR联合检测生存分析显示,LtHm组患者(39例)的3年生存率为69.2%,HtLm(20例)组患者的3年生存率为40.0%,两组总体生存率具有统计学差异(P=0.012),该差异在术后辅助化疗患者中仍存在(P=0.011).结论:辅助化疗组患者中LtHm组总体生存率显著高于HtLm组,LtLm组患者较HtHm组患者更易从氟尿嘧啶类药物辅助化疗中获益.     

PIN1在胃癌组织中的表达及其预后意义

目的 探讨肽基脯氨酰顺反异构酶（PIN1）在胃癌中的表达及其与临床病理学特征及预后的关系。方法 应用组织芯片、免疫组化技术检测134例胃癌组织及对应癌旁组织中PIN1蛋白的表达情况,分析其与临床病理特征及预后的关系。结果胃癌组织中PIN1阳性表达率为33.6％（45／134）,癌旁组织为21.6％（29／134）,差异有统计学意义（P＜0.05）。PIN1表达与胃癌患者TNM分期和远处转移有关（P=0.007,P=0.010）,与其他临床病理特征无关（P＞0.05）。PIN1阳性患者的5年生存率为35.7％,阴性患者为50.6％,差异有统计学意义（P＜0.05）。Cox多因素分析显示,PIN1表达不是胃癌的独立预后因素,而pTNM分期和Lauren分型是胃癌的独立预后因素。结论 胃癌组织中存在PIN1阳性表达,并与TNM分期和远处转移及预后密切相关,可能是潜在的胃癌治疗靶点。