AIM To investigate the impact of thymidylate synthase(TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer(m CRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectivel...AIM To investigate the impact of thymidylate synthase(TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer(m CRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectively from records of consecutive patients with m CRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region(UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression(and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.RESULTS The analysis recovered 89 patients with m CRC(46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients(51.7%) had colon cancer and 43(48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy(5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo(range 0-119.8), 85 patients(95.5%) experienced disease progression, and 63 deaths(70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death(P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele(genotypes ins/ins and ins/loss of heterozygosity(LOH) linked with high TYMS expression) tumors with del/del genotype(low expression group) and tumors with ins/del or del/LOH(intermediate expression group) have lower risk for disease progression(HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death(HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally,KRAS mutation was associated independently with the risk of disease progression(HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death(HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively).CONCLUSION The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in m CRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.展开更多
目的联合检测EGFR野生型非小细胞肺癌（NSCLC）患者的ERCC1、RRM1、TYMS和TUBB3的mRNA表达水平差异,以探究4种基因的表达水平对化疗效果及预后的影响。方法将353例NSCLC患者的标本通过xTAG-液相芯片法筛选出EGFR野生型患者,采用实时荧...目的联合检测EGFR野生型非小细胞肺癌（NSCLC）患者的ERCC1、RRM1、TYMS和TUBB3的mRNA表达水平差异,以探究4种基因的表达水平对化疗效果及预后的影响。方法将353例NSCLC患者的标本通过xTAG-液相芯片法筛选出EGFR野生型患者,采用实时荧光定量PCR检测标本中4种基因的mRNA表达水平。EGFR野生型患者中4种基因均高表达的为高表达组,否则为低表达组,比较两组患者接受化疗后的中位无进展生存期及中位总生存期。结果遴选出EGFR野生型NSCLC患者227例,除吸烟与不吸烟者外,其他不同特征型患者之间4种基因mRNA表达水平之间差异无统计学意义（P〉0.05）。野生型高表达组有27例,野生型低表达组有53例,两组患者客观缓解率（ORR）（14.8%vs 41.5%,P〈0.05）、疾病控制率（DCR）（40.7%vs 81.1%,P〈0.05）、中位无进展生存期（月）（3.3 vs 4.9,P=0.001）与中位总生存期（月）（7.1 vs 8.1,P=0.048）间差异均有统计学意义。Cox多因素分析显示,4种基因高表达为EGFR野生型NSCLC患者化疗预后的独立危险因素（HR=1.92;95%CI：1.10~3.42）。结论 EGFR野生型NSCLC患者肿瘤组织的ERCC1、TYMS、TUBB3和RRM1 mRNA为高表达水平时,预示其对化疗药物具有耐药性。联合检测4种基因的表达有利于化疗方案的选择。展开更多
基金Supported by Kapodistrias,National and Kapodistrian University of Athens,No.70/3/8006(Pythagoras II,EPEAEK II,GSRT)and No.70/3/9114Spathis A was supported during data collection by No.70/3/8462[PENED European Social Fund(75%)and the Greek Ministry of Development-GSRT(25%)]
文摘AIM To investigate the impact of thymidylate synthase(TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer(m CRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectively from records of consecutive patients with m CRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region(UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression(and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.RESULTS The analysis recovered 89 patients with m CRC(46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients(51.7%) had colon cancer and 43(48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy(5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo(range 0-119.8), 85 patients(95.5%) experienced disease progression, and 63 deaths(70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death(P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele(genotypes ins/ins and ins/loss of heterozygosity(LOH) linked with high TYMS expression) tumors with del/del genotype(low expression group) and tumors with ins/del or del/LOH(intermediate expression group) have lower risk for disease progression(HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death(HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally,KRAS mutation was associated independently with the risk of disease progression(HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death(HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively).CONCLUSION The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in m CRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.
文摘目的联合检测EGFR野生型非小细胞肺癌（NSCLC）患者的ERCC1、RRM1、TYMS和TUBB3的mRNA表达水平差异,以探究4种基因的表达水平对化疗效果及预后的影响。方法将353例NSCLC患者的标本通过xTAG-液相芯片法筛选出EGFR野生型患者,采用实时荧光定量PCR检测标本中4种基因的mRNA表达水平。EGFR野生型患者中4种基因均高表达的为高表达组,否则为低表达组,比较两组患者接受化疗后的中位无进展生存期及中位总生存期。结果遴选出EGFR野生型NSCLC患者227例,除吸烟与不吸烟者外,其他不同特征型患者之间4种基因mRNA表达水平之间差异无统计学意义（P〉0.05）。野生型高表达组有27例,野生型低表达组有53例,两组患者客观缓解率（ORR）（14.8%vs 41.5%,P〈0.05）、疾病控制率（DCR）（40.7%vs 81.1%,P〈0.05）、中位无进展生存期（月）（3.3 vs 4.9,P=0.001）与中位总生存期（月）（7.1 vs 8.1,P=0.048）间差异均有统计学意义。Cox多因素分析显示,4种基因高表达为EGFR野生型NSCLC患者化疗预后的独立危险因素（HR=1.92;95%CI：1.10~3.42）。结论 EGFR野生型NSCLC患者肿瘤组织的ERCC1、TYMS、TUBB3和RRM1 mRNA为高表达水平时,预示其对化疗药物具有耐药性。联合检测4种基因的表达有利于化疗方案的选择。
