错配修复/微卫星不稳定性对晚期结直肠癌化疗敏感性及预后的影响
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摘要
目的探究错配修复/微卫星不稳定性(MSI)在晚期结直肠癌化疗敏感性及临床转归中的意义。方法收集2009年12月～2016年12月在扬州大学附属医院肿瘤科的接受FOLFOX或XELOX一线方案化疗的181例晚期结直肠癌患者的原发肿瘤组织,采用免疫组化方法检测肿瘤组织MLH1、PMS2、MSH2、MSH6 4种蛋白的表达情况,并分为MSI组(18例)和微卫星稳定组(MSS组,163例),比较两组在化疗敏感性和预后中的差异。结果除了病变部位外(P <0.05),其他临床特征在MSI组及MSS组中差异均无统计学意义(P> 0.05)。采用Kaplan-Meier生存曲线对随访资料进行分析,MSI组和MSS组的患者总体生存时间差异无统计学意义(P> 0.05)。化疗敏感性方面,MSI组和MSS组的化疗总有效率差异无统计学意义(P> 0.05),但是MSI组疾病控制率显著高于MSS组,差异有统计学意义(P <0.05)。结论 MSI状态与晚期结直肠癌患者的总生存时间无关,与疾病控制率有关。因此,MSI可以作为评估晚期结直肠癌患者化疗效果的重要指标。
Objective To investigate the significance of mismatch repair/microsatellite instability(MSI) in the chemotherapy sensitivity and prognosis of late-stage colorectal cancer(CRC). Methods From December 2009 to December 2016,in Affiliated Hospital of Yangzhou University, 181 primary tumor tissues were collected from CRC patients who received first-line chemotherapy(FOLFOX or XELOX). Immunohistochemistry was used to detect the expression of MLH1,PMS2, MSH2 and MSH6 in tumor tissues. Based on the staining results, they were divided into MSI group(18 cases) and microsatellite stability(MSS) group(163 cases). The intergroup difference in chemotherapy sensitivity and prognosis were analyzed. Results Except for tumor location(P < 0.05), the differences were not statistically significant in clinical features between two groups(P > 0.05). Kaplan-Meier model was used to analyze follow-up data, there was no statistically significant difference in patient prognosis of two groups(P > 0.05). In chemotherapy sensitivity, there was no statistically significant difference in the total effective rate of two groups(P > 0.05). However, disease control rate of MSI group was significant higher than MSS group, the difference was statistically significant(P < 0.05). Conclusion Although MSI status is not related with the prognosis of late-stage CRC patients, but it is correlated with disease control rate. Therefore, MSI can act as an important marker for evaluating the chemotherapy efficacy in late-stage CRC patients.
Objective To investigate the significance of mismatch repair/microsatellite instability(MSI) in the chemotherapy sensitivity and prognosis of late-stage colorectal cancer(CRC). Methods From December 2009 to December 2016,in Affiliated Hospital of Yangzhou University, 181 primary tumor tissues were collected from CRC patients who received first-line chemotherapy(FOLFOX or XELOX). Immunohistochemistry was used to detect the expression of MLH1,PMS2, MSH2 and MSH6 in tumor tissues. Based on the staining results, they were divided into MSI group(18 cases) and microsatellite stability(MSS) group(163 cases). The intergroup difference in chemotherapy sensitivity and prognosis were analyzed. Results Except for tumor location(P < 0.05), the differences were not statistically significant in clinical features between two groups(P > 0.05). Kaplan-Meier model was used to analyze follow-up data, there was no statistically significant difference in patient prognosis of two groups(P > 0.05). In chemotherapy sensitivity, there was no statistically significant difference in the total effective rate of two groups(P > 0.05). However, disease control rate of MSI group was significant higher than MSS group, the difference was statistically significant(P < 0.05). Conclusion Although MSI status is not related with the prognosis of late-stage CRC patients, but it is correlated with disease control rate. Therefore, MSI can act as an important marker for evaluating the chemotherapy efficacy in late-stage CRC patients.
引文
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[12]秦云,梁莉萍,郑兴征,等.免疫组织化学法检测结直肠癌四种DNA错配修复蛋白表达缺失对判断肿瘤微卫星状态的价值[J].中华病理学杂志,2015,44(10):704-708.
[13]Jin P,Wang DZ,Lyu CX.Mismatch repair protein h MLH1,but not hMSH2,enhances estrogen-induced apoptosis of colon cancer cells[J].J Cancer,2017,8(16):3232-3241.
[14]Karahan B,Argon A,Yldrm M,et al.Relationship between MLH-1,MSH-2,PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer[J].Int JClin Exp Pathol,2015,8(4):4044-4053.
[15]Takehara Y,Nagasaka T,Nyuya A,et al.Accuracy of four mononucleotide-repeat markers for the identification of DNA mismatch-repair deficiency in solid tumors[J].JTransl Med,2018,16(1):5.
[16]Ozkara S,Sari B,Yesil A,et al.Evaluation of colorectal adenocarcinomas at single-institution with respect to microsatellite instability[J].Chirurgia(Bucur),2013,108(4):473-477.
[17]Li G,Hu F,Yuan F,et al.Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China[J].J Cancer Res Clin Oncol,2015,141(8):1393-1404.
[18]陈寅波,刘卓,钱俊,等.DNA错配修复基因hMLH1与hMSH2在结直肠癌合并慢性血吸虫肠病与散发型结直肠癌中表达的差异研究[J].中华胃肠外科杂志,2016,19(1):75-79.
[19]Matsuzaki K,Borel V,Adelman CA,et al.FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway[J].Genes Dev,2015,29(24):2532-2546.
[20]李政.错配修复蛋白在结直肠癌中的临床意义及其与BRAF~(V600E)突变相关性研究[D].石家庄:河北医科大学,2017.
[21]Des Guetz G,Schischmanoff O,Nicolas P,et al.Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer?A systematic review with meta-analysis[J].Eur J Cancer,2009,45(10):1890-1896.
[22]吴宇辰,张长胜,梁斐,等.微卫星不稳定状态对Ⅳ期结直肠癌患者化疗反应性和预后的影响[J].中国癌症杂志,2015,25(7):522-528.
[2]Siegel RL,Miller KD,Fedewa SA,et al.Colorectal cancer statistics,2017[J].CA Cancer J Clin,2017,67(3):177-193.
[3]Walker M,O′Sullivan B,Perakath B,et al.Selecting patients with young-onset colorectal cancer for mismatch repair gene analysis[J].Br J Surg,2007,94(12):1567-1571.
[4]Mendillo ML,Mazur DJ,Kolodner RD.Analysis of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 and MLH1-PMS1 complexes with DNA using a reversible DNA end-blocking system[J].J Biol Chem,2005,280(23):22245-22257.
[5]Brueckl WM,Moesch C,Brabletz T,et al.Relationship between microsatellite instability,response and survival in palliative patients with colorectal cancer undergoing firstline chemotherapy[J].Anticancer Res,2003,23(2C):1773-1777.
[6]Müller CI,Schulmann K,Reinacher-Schick A,et al.Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing first-line chemotherapy.A report of the AIO Colorectal Study Group[J].Int J Colorectal Dis,2008,23(11):1033-1039.
[7]Carethers JM,Koi M,Tseng-Rogenski SS.EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression[J].Genes(Basel),2015,6(2):185-205.
[8]Press MO,Carlson KD,Queitsch C.The overdue promise of short tandem repeat variation for heritability[J].Trends Genet,2014,30(11):504-512.
[9]Gadgil R,Barthelemy J,Lewis T,et al.Replication stalling and DNA microsatellite instability[J].Biophys Chem,2017,225:38-48.
[10]Gupta R,Sinha S,Paul RN.The impact of microsatellite stability status in colorectal cancer[J].Curr Probl Cancer,2018,42(6):548-559.
[11]Nojadeh JN,Behrouz Sharif S.Microsatellite instability in colorectal cancer[J].Excli J,2018,17:159-168.
[12]秦云,梁莉萍,郑兴征,等.免疫组织化学法检测结直肠癌四种DNA错配修复蛋白表达缺失对判断肿瘤微卫星状态的价值[J].中华病理学杂志,2015,44(10):704-708.
[13]Jin P,Wang DZ,Lyu CX.Mismatch repair protein h MLH1,but not hMSH2,enhances estrogen-induced apoptosis of colon cancer cells[J].J Cancer,2017,8(16):3232-3241.
[14]Karahan B,Argon A,Yldrm M,et al.Relationship between MLH-1,MSH-2,PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer[J].Int JClin Exp Pathol,2015,8(4):4044-4053.
[15]Takehara Y,Nagasaka T,Nyuya A,et al.Accuracy of four mononucleotide-repeat markers for the identification of DNA mismatch-repair deficiency in solid tumors[J].JTransl Med,2018,16(1):5.
[16]Ozkara S,Sari B,Yesil A,et al.Evaluation of colorectal adenocarcinomas at single-institution with respect to microsatellite instability[J].Chirurgia(Bucur),2013,108(4):473-477.
[17]Li G,Hu F,Yuan F,et al.Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China[J].J Cancer Res Clin Oncol,2015,141(8):1393-1404.
[18]陈寅波,刘卓,钱俊,等.DNA错配修复基因hMLH1与hMSH2在结直肠癌合并慢性血吸虫肠病与散发型结直肠癌中表达的差异研究[J].中华胃肠外科杂志,2016,19(1):75-79.
[19]Matsuzaki K,Borel V,Adelman CA,et al.FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway[J].Genes Dev,2015,29(24):2532-2546.
[20]李政.错配修复蛋白在结直肠癌中的临床意义及其与BRAF~(V600E)突变相关性研究[D].石家庄:河北医科大学,2017.
[21]Des Guetz G,Schischmanoff O,Nicolas P,et al.Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer?A systematic review with meta-analysis[J].Eur J Cancer,2009,45(10):1890-1896.
[22]吴宇辰,张长胜,梁斐,等.微卫星不稳定状态对Ⅳ期结直肠癌患者化疗反应性和预后的影响[J].中国癌症杂志,2015,25(7):522-528.