微卫星不稳定结直肠癌临床病理特征及生存预后
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摘要
目的国内外已有学者提出微卫星不稳定(microsatellite instability,MSI)状态可能是影响结直肠癌(colorectal cancer,CRC)患者预后的因素,同时提出微卫星不稳定结直肠癌患者存在较为特殊的临床病理特征,本研究旨在探讨微卫星不稳定CRC的临床病理特征及生存预后。方法应用免疫组织化学方法检测2010-03-24-2015-12-24济南市第四人民医院60例CRC组织中人MutL蛋白同系物1(human mutl homologue 1,hMLH1)、人MutS蛋白同系物2(human muts homologue 2,hMSH2)及人MutS蛋白同系物6(human muts homologue 6,hMSH6)3种DNA错配修复蛋白表达缺失情况,判断肿瘤微卫星不稳定状态,并分析高度微卫星不稳定(microsatellite instability-high,MSI-H)和低度微卫星不稳定(microsatellite instability-low,MSI-L)/微卫星稳定(microsatellite stable,MSS)不同组别间的临床病理特征及生存预后情况;应用Cox风险比例模型对可能影响CRC患者预后的因素进行多因素分析。结果 60例CRC患者的肿瘤组织中MSI-H为40.0%(24/60),MSI-L为31.7%(19/60),MSS为28.3%(17/60)。MSI-H的CRC患者,与MSS和MSI-L患者相比,好发于右半结肠(χ~2=6.279,P=0.043),黏液腺癌多见(χ~2=6.025,P=0.049);3组在性别、年龄、分期、肿瘤浸润深度、淋巴结转移和分化程度差异无统计学意义。MSI-H患者的中位无病生存期(disease-free survival,DFS)为21个月,明显长于MSS的11个月及MSI-L的13个月,χ~2=7.994,P=0.018。多因素Cox分析结果显示,淋巴结转移(P=0.013)和MSI(P=0.018)为CRC患者DFS的独立预后因素。结论 MSI-H的CRC患者与MSI-L及MSS相比,具有独特的临床病理特征且预后相对较好。检测MSI状态对提高CRC治疗水平,及改善预后有重要的临床意义。
OBJECTIVE Some scholars suggest that microsatellite instability(MSI)may become an influence factors for the prognosis of patients with colorectal cancer and they also suggest that patients with microsatellite instability have special clinicalpathologic features.The purpose of this study was to explore the colinicopathologic features and prognosis of colorectal cancer patients with microsatellite instability.METHODS Immunohistochemistry was used to detect the human mutl homologue 1(hMLH1),human muts homologue 2(hMSH2)or Human muts homologue 6(hMSH6)protein expression in the tumor tissues from 60 cases of Fourth People's Hospital of Jinan(2010-03-24-2015-12-24)to predict tumor MSI status and analyze colinicopathologic features and prognosis of colorectal cancer patients with Microsatellite instability-high(MSI-H)and Microsatellite instability-low(MSI-L)/Microsatellite stable(MSS).Clinicopathologic factors related to prognosis of patients with colorectal cancer were analyzed by multivariate COX proportional hazards model.RESULTS The MSI-H,MSI-L and MSS in the tumor tissues from 60 patients were 40.0%(24/60),31.7%(19/60),28.3%(17/60),respectively.MSI-H was good in the right colon(χ~2=6.279,P=0.043),mucinous adenocarcinoma(χ~2=6.025,P=0.049).There was no significant difference in gender,age,clinical stage,depth of tumor invasion,lymph node metastasis and differentiation degree among the three groups:The median Disease-free survival(DFS)of MSI-H significantly longer than MSS and MSI-L patients(χ~2=7.994,P=0.018),there median Disease-free survival were 21 months,11months,13 months,respectively.Multivariate analysis revealed that lymph node metastasis(P=0.013)and MSI(P=0.018)were independent prognostic factors of DFS in patients with colorectal cancer.CONCLUSIONS Compared with MSI-L and MSS,MSI-H colorectal cancer patients have unique clinical and pathological features and have relatively good prognosis.Detection of MSI status is very important for improving the level of colorectal cancer treatment and the prognosis.
OBJECTIVE Some scholars suggest that microsatellite instability(MSI)may become an influence factors for the prognosis of patients with colorectal cancer and they also suggest that patients with microsatellite instability have special clinicalpathologic features.The purpose of this study was to explore the colinicopathologic features and prognosis of colorectal cancer patients with microsatellite instability.METHODS Immunohistochemistry was used to detect the human mutl homologue 1(hMLH1),human muts homologue 2(hMSH2)or Human muts homologue 6(hMSH6)protein expression in the tumor tissues from 60 cases of Fourth People's Hospital of Jinan(2010-03-24-2015-12-24)to predict tumor MSI status and analyze colinicopathologic features and prognosis of colorectal cancer patients with Microsatellite instability-high(MSI-H)and Microsatellite instability-low(MSI-L)/Microsatellite stable(MSS).Clinicopathologic factors related to prognosis of patients with colorectal cancer were analyzed by multivariate COX proportional hazards model.RESULTS The MSI-H,MSI-L and MSS in the tumor tissues from 60 patients were 40.0%(24/60),31.7%(19/60),28.3%(17/60),respectively.MSI-H was good in the right colon(χ~2=6.279,P=0.043),mucinous adenocarcinoma(χ~2=6.025,P=0.049).There was no significant difference in gender,age,clinical stage,depth of tumor invasion,lymph node metastasis and differentiation degree among the three groups:The median Disease-free survival(DFS)of MSI-H significantly longer than MSS and MSI-L patients(χ~2=7.994,P=0.018),there median Disease-free survival were 21 months,11months,13 months,respectively.Multivariate analysis revealed that lymph node metastasis(P=0.013)and MSI(P=0.018)were independent prognostic factors of DFS in patients with colorectal cancer.CONCLUSIONS Compared with MSI-L and MSS,MSI-H colorectal cancer patients have unique clinical and pathological features and have relatively good prognosis.Detection of MSI status is very important for improving the level of colorectal cancer treatment and the prognosis.
引文
[1]郑树,张苏展,黄彦钦.结直肠癌研究30年回顾和现状[J].实用肿瘤杂志,2016,31(1):2-5.
[2]Worthley DL,Leggett BA.Colorectal cancer:molecular features and clinical opportunities[J].Clin Biochem Rev,2010,31(2):31-38.
[3]Ribic CM,Sargent DJ,Moore MJ,et al.Tumor microsatelliteinstability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer[J].N Engl J Med,2003,349(3):247-257.
[4]de la Chapelle A,Hampel H.Clinical relevance of microsatellite instability in colorectal cancer[J].J Clin Oncol,2010,28(20):3380-3387.
[5]Valle L,Perea J,Carbonell P,et al.Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status[J].J Clin Oncol,2007,25(7):781-786.
[6]黄小华,刘叶,徐炎良.FOLFOX6方案治疗晚期结直肠癌的疗效与安全性分析[J].实用癌症杂志,2016,31(5):801-803.
[7]刘沛华.奥沙利铂、亚叶酸钙及5-氟尿嘧啶治疗晚期结直肠癌46例[J].中国临床研究,2014,27(1):39-40.
[8]陆晓,符炜,陆屸,等.结直肠癌根治术后FOLFOX方案辅助化疗的临床疗效[J].江苏医药,2015,41(15):1804-1806.
[9]张克新,赵洁敏,邹永祎,等.76例结直肠癌患者根治术后FOLFOX4方案辅助化疗的临床观察[J].临床荟萃,2014,29(11):1246-1250.
[10]Niessen RC,Berends MJ,Wu Y,et al.Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer[J].Gut,2006,55(12):1781-1788.
[11]Wyman AR,White R.A highly polymorphic locus in human DNA[J].Pro Nat Acad Sci U S A,1980,77(11):6754-6758.
[12]Allegra CJ,Kim G,Kirsch IR.Microsatellite instability in colon cancer[J].N Engl J Med,2003,349(18):1774-1776.
[13]张晓云,张春雁,王延文,等.结直肠癌DNA错配修复蛋白的表达及临床病理学意义[J].中国医药生物技术,2016,11(2):123-127.
[14]彭俊玲,汤涛,叶祖禄,等.散发性结直肠癌微卫星不稳定状态与错配修复蛋白表达缺失及临床病理特征的相关性[J].中国肿瘤生物治疗杂志,2015,22(4):479-483.
[15]Kim ST,Lee J,Park SH,et al.Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy[J].Cancer Chemother Pharmacol,2010,66(4):659-667.
[16]Guastadisegni C,Colafranceschi M,Ottini L,et al.Microsatellite instability as a marker of prognosis and response to therapy:a meta-analysis of colorectal cancer survival data[J].Eur J Cancer,2010,46(15):2788-2798.
[17]孟文建,王玲,于永扬,等.微卫星不稳定在散发性Ⅱ~Ⅲ期直肠癌中的意义[J].重庆医学,2010,39(18):2420-2426.
[18]Yang G,Zheng HX,Wu LN,et al.Relationship between microsatellite instability and hepatocyte growth factor expression and their prognostic significance in colorectal cancer[J].Zhonghua Zhong Liu Za Zhi,2016,38(4):283-288.
[19]张宝昕,潘宏达,高兆亚,等.结肠癌患者预后临床病理的多因素分析[J].世界华人消化杂志,2014,22(15):2202-2207.
[2]Worthley DL,Leggett BA.Colorectal cancer:molecular features and clinical opportunities[J].Clin Biochem Rev,2010,31(2):31-38.
[3]Ribic CM,Sargent DJ,Moore MJ,et al.Tumor microsatelliteinstability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer[J].N Engl J Med,2003,349(3):247-257.
[4]de la Chapelle A,Hampel H.Clinical relevance of microsatellite instability in colorectal cancer[J].J Clin Oncol,2010,28(20):3380-3387.
[5]Valle L,Perea J,Carbonell P,et al.Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status[J].J Clin Oncol,2007,25(7):781-786.
[6]黄小华,刘叶,徐炎良.FOLFOX6方案治疗晚期结直肠癌的疗效与安全性分析[J].实用癌症杂志,2016,31(5):801-803.
[7]刘沛华.奥沙利铂、亚叶酸钙及5-氟尿嘧啶治疗晚期结直肠癌46例[J].中国临床研究,2014,27(1):39-40.
[8]陆晓,符炜,陆屸,等.结直肠癌根治术后FOLFOX方案辅助化疗的临床疗效[J].江苏医药,2015,41(15):1804-1806.
[9]张克新,赵洁敏,邹永祎,等.76例结直肠癌患者根治术后FOLFOX4方案辅助化疗的临床观察[J].临床荟萃,2014,29(11):1246-1250.
[10]Niessen RC,Berends MJ,Wu Y,et al.Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer[J].Gut,2006,55(12):1781-1788.
[11]Wyman AR,White R.A highly polymorphic locus in human DNA[J].Pro Nat Acad Sci U S A,1980,77(11):6754-6758.
[12]Allegra CJ,Kim G,Kirsch IR.Microsatellite instability in colon cancer[J].N Engl J Med,2003,349(18):1774-1776.
[13]张晓云,张春雁,王延文,等.结直肠癌DNA错配修复蛋白的表达及临床病理学意义[J].中国医药生物技术,2016,11(2):123-127.
[14]彭俊玲,汤涛,叶祖禄,等.散发性结直肠癌微卫星不稳定状态与错配修复蛋白表达缺失及临床病理特征的相关性[J].中国肿瘤生物治疗杂志,2015,22(4):479-483.
[15]Kim ST,Lee J,Park SH,et al.Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy[J].Cancer Chemother Pharmacol,2010,66(4):659-667.
[16]Guastadisegni C,Colafranceschi M,Ottini L,et al.Microsatellite instability as a marker of prognosis and response to therapy:a meta-analysis of colorectal cancer survival data[J].Eur J Cancer,2010,46(15):2788-2798.
[17]孟文建,王玲,于永扬,等.微卫星不稳定在散发性Ⅱ~Ⅲ期直肠癌中的意义[J].重庆医学,2010,39(18):2420-2426.
[18]Yang G,Zheng HX,Wu LN,et al.Relationship between microsatellite instability and hepatocyte growth factor expression and their prognostic significance in colorectal cancer[J].Zhonghua Zhong Liu Za Zhi,2016,38(4):283-288.
[19]张宝昕,潘宏达,高兆亚,等.结肠癌患者预后临床病理的多因素分析[J].世界华人消化杂志,2014,22(15):2202-2207.