胃癌组织中p53蛋白表达和微卫星不稳定及其与预后的相关性研究
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摘要
[目的]探讨胃癌组织中p53蛋白表达与微卫星不稳定(microsatellite instability,MSI)与胃癌临床病理特征及预后的关系。[方法]选取行胃癌手术患者104例,采用免疫组织化学法检测肿瘤组织中p53蛋白和错配修复蛋白(mismatch repair protein,MMRP)(MLH1、MSH2、MSH6和PMS2)表达,分析p53表达和MSI与患者临床病理参数的关系。术后患者随访2年,采用Logistics回归分析影响患者预后的危险因素。[结果]胃癌组织中p53、MLH1、MSH2、MSH6和PMS2均定位于肿瘤细胞核。104例胃癌中p53阳性46例(44.23%);MMRP阳性65例(62.50%),39例MMRP表达缺失(37.50%),其中MLH1、MSH2、MSH62及PMS表达缺失分别为25例(24.04%)、19例(18.27%)、18例(17.31%)和22例(21.15%)。胃癌低分化组及Ⅲ期组中p53阳性表达率显著降低(P<0.05)。p53在癌组织中的表达与MSI呈负相关(r=-0.486,P<0.05)。Logistic多因素回归分析显示,TNM分期、MSI和p53阴性是影响患者预后的独立危险因素。[结论]胃癌组织中p53与MSI呈负相关。对胃癌组织监测p53与MSI对制定给药方案及评估预后具有重要意义。
[Objective] To investigate the relationship of p53 expression and microsatellite instability(MSI) with the clinicopathological features and prognosis of gastric cancer. [Methods] One hundred and four patients with gastric carcinoma undergoing gastrectomy were enrolled. Expression of p53 protein and mismatch repair protein(MMRP) MLH1,MSH2,MSH6 and PMS2 in gastric carcinoma tissues were detected by immunohistochemistry. The relationship between p53 expression and MSI with clinicopatholigical parameters were analyzed. All patients were followed up for 2 years,the risk factors affecting the prognosis of patients was analyzed by Logistic regression.[Results] The expressions of P53,MLH1,MSH2,MSH6 and PMS2 were localized in nuclei in gastric carcinoma cells. Among 104 cases of gastric cancer,46 cases were p53 positive(44.23%),65 cases(62.50%) were MMRP positive and 39 cases(37.50%) were MMRP negative. Among them,the missing of MLH1,MSH2,MSH6 and PMS2 was 25 cases(24.04%),19 cases(18.27%),18 cases(17.31%) and 22 cases(21.15%),respectively. The expression of p53 was significantly lower in the poorly differentiated and stage Ⅲ gastric carcinoma(P<0.05). The expression of p53 was negatively correlated with MSI(r=-0.486,P<0.05). Logistic multivariate regression analysis showed that higher TNM staging,MSI and negative p53 were independent risk factors for poor prognosis in gastric carcinoma. [Conclusion] P53 is negatively correlated with MSI in gastric cancer tissues. The detection of p53 expression and MSI is of value for treatment monitoring and prognosis of gastric carcinoma patients.
[Objective] To investigate the relationship of p53 expression and microsatellite instability(MSI) with the clinicopathological features and prognosis of gastric cancer. [Methods] One hundred and four patients with gastric carcinoma undergoing gastrectomy were enrolled. Expression of p53 protein and mismatch repair protein(MMRP) MLH1,MSH2,MSH6 and PMS2 in gastric carcinoma tissues were detected by immunohistochemistry. The relationship between p53 expression and MSI with clinicopatholigical parameters were analyzed. All patients were followed up for 2 years,the risk factors affecting the prognosis of patients was analyzed by Logistic regression.[Results] The expressions of P53,MLH1,MSH2,MSH6 and PMS2 were localized in nuclei in gastric carcinoma cells. Among 104 cases of gastric cancer,46 cases were p53 positive(44.23%),65 cases(62.50%) were MMRP positive and 39 cases(37.50%) were MMRP negative. Among them,the missing of MLH1,MSH2,MSH6 and PMS2 was 25 cases(24.04%),19 cases(18.27%),18 cases(17.31%) and 22 cases(21.15%),respectively. The expression of p53 was significantly lower in the poorly differentiated and stage Ⅲ gastric carcinoma(P<0.05). The expression of p53 was negatively correlated with MSI(r=-0.486,P<0.05). Logistic multivariate regression analysis showed that higher TNM staging,MSI and negative p53 were independent risk factors for poor prognosis in gastric carcinoma. [Conclusion] P53 is negatively correlated with MSI in gastric cancer tissues. The detection of p53 expression and MSI is of value for treatment monitoring and prognosis of gastric carcinoma patients.
引文
[1]Park JS,Kim J,Elghiaty A,et al.Recent global trends in testicular cancer incidence and mortality[J].Medicine(Baltimore),2018,97(37):e12390.
[2]Zuo TT,Zheng RS,Zeng HM,et al.Epidemiology of stomach cancer in China[J].Chinese Journal of Clinical Oncology,2017,44(1):52-58.[左婷婷,郑荣寿,曾红梅,等.中国胃癌流行病学现状[J].中国肿瘤临床,2017,44(1):52-58.]
[3]Hu JK,Chen XZ.Selection and assessment of digestive tract reconstruction patterns for gastric cancer[J].Chinese Journal of Digestive Surgery,2013,12(1):25-29.[胡建昆,陈心足.胃癌手术消化道重建方式的选择及评价[J].中华消化外科杂志,2013,12(1):25-29.]
[4]Liao Y,Deng Y,Fu JW.Progress in research on molecular mechanism of gastric cancer[J].China Cancer,2014,23(1):58-62.[廖毅,邓媛,傅建伟.胃癌分子机制的研究进展[J].中国肿瘤,2014,23(1):58-62.]
[5]Quandt J,Schlude C,Bartoschek M,et al.Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses[J].Oncoimmunology,2018,7(12):e1500671.
[6]Qin Y,Liang LP,Zheng XZ,et al.Value of detection of DNA mismatch repair proteins deficiency by immunohistochemistry in predicting tumor microsatellite status[J].Chinese Journal of Pathology,2015,44(10):704-708.[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.]
[7]Sun D,Fan YJ,Xu H,et al.BRCA1 microsatellite instability in endometrial carcinoma and its relationship with clinical pathology[J].The Journal of Practical Medicine,2015,31(22):3717-3719.[孙丹,范余娟,徐红,等.子宫内膜癌中人类乳腺癌易感基因1微卫星不稳定性及其与临床病理的关系[J].实用医学杂志,2015,31(22):3717-3719.]
[8]Ye M,Sun DZ,Wei PK.The DNA microsatellite instability and gastric carcinoma[J].Chinese Journal of Clinicians(Electronic Edition),2013,(9):151-152.[叶敏,孙大志,魏品康.DNA微卫星不稳定与胃癌[J].中华临床医师杂志(电子版),2013,(9):151-152.]
[9]De MC,Forman D,Plummer M.Gastric cancer:epidemiology and risk factors[J].Gastroenterol Clin N,2013,107(3):230-236.
[10]Ahn HS,Kim SH,Kodera Y,et al.Gastric cancer staging with radiologic imaging modalities and UICC staging system[J].Dig Surg,2013,30(2):142-149.
[11]Teodoro JG,Parker AE,Zhu X,et al.p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolylhydroxylase.[J].Science,2006,313(5789):968-971.
[12]Alexandrov LB,Nikzainal S,Wedge DC,et al.Signatures of mutational processes in human cancer[J].Nature,2013,500(7463):415-21.
[13]Nan HM,Song YJ,Yun HY,et al.Effects of dietary intake and genetic factors on hypermethylation of the hMLH1gene promoter in gastric cancer.[J].World J Gastroenterol,2005,11(25):3834-3841.
[14]Tzanakis NE,Peros G,Karakitsos P,et al.Prognostic significance of p53 and Ki67 proteins expression in Greek gastric carcinoma patients[J].Acta Chir Belg,2009,109(5):606-611.
[15]Ohashi S,Okamura S,Urano F,et al.Clinicopathological variables associated with lymph node metastasis in submucosal invasive gastric carcinoma[J].Gastric Carcinoma,2007,10(4):241-250.
[16]Zhang JQ,Fu GZ,Wu HH,et al.Germline mutation analysis,microsatellite instability and clinical pathology in Hazakh in China hereditary nonpolyposis colorectal cancer pedigree[J].Chinese Journal of Experimental Surgery,2014,31(2):245-247.[张剑权,符国珍,吴海红,等.遗传性非息肉病性大肠癌微卫星不稳定临床病理和错配修复基因变异的研究[J].中华实验外科杂志,2014,31(2):245-247.]
[17]Ma Y,Tao Y.Research progress of MSI colorectal cancer[J].Practical Oncology Journal,2017,31(4):376-380.[马悦,陶冀.MSI结直肠癌的研究进展[J].实用肿瘤学杂志,2017,31(4):376-380.]
[18]Copija A,Waniczek D,Witko A,et al.Clinical significance and prognostic relevance of microsatellite instability in sporadic colorectal carcinoma patients[J].Int J Mol Sci,2017,18(1):107.
[19]Hernni-Eusébio J,Barbosa E.Phenotypic heterogeneity by germline mismatch repair gene defect in Lynch syndrome patients[J].Acta Med Port,2016,29(10):587-596.
[20]Palli D,Russo A,Ottini L,et al.Red meat,family history,and increased risk of gastric cancer with microsatellite instability.[J].Cancer Res,2001,61(14):5415-5419.
[21]Saridaki Z.Prognostic and predictive significance of MSIin stagesⅡ/Ⅲcolon carcer[J].World J Gastroenterol,2014,20(22):6809.
[2]Zuo TT,Zheng RS,Zeng HM,et al.Epidemiology of stomach cancer in China[J].Chinese Journal of Clinical Oncology,2017,44(1):52-58.[左婷婷,郑荣寿,曾红梅,等.中国胃癌流行病学现状[J].中国肿瘤临床,2017,44(1):52-58.]
[3]Hu JK,Chen XZ.Selection and assessment of digestive tract reconstruction patterns for gastric cancer[J].Chinese Journal of Digestive Surgery,2013,12(1):25-29.[胡建昆,陈心足.胃癌手术消化道重建方式的选择及评价[J].中华消化外科杂志,2013,12(1):25-29.]
[4]Liao Y,Deng Y,Fu JW.Progress in research on molecular mechanism of gastric cancer[J].China Cancer,2014,23(1):58-62.[廖毅,邓媛,傅建伟.胃癌分子机制的研究进展[J].中国肿瘤,2014,23(1):58-62.]
[5]Quandt J,Schlude C,Bartoschek M,et al.Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses[J].Oncoimmunology,2018,7(12):e1500671.
[6]Qin Y,Liang LP,Zheng XZ,et al.Value of detection of DNA mismatch repair proteins deficiency by immunohistochemistry in predicting tumor microsatellite status[J].Chinese Journal of Pathology,2015,44(10):704-708.[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.]
[7]Sun D,Fan YJ,Xu H,et al.BRCA1 microsatellite instability in endometrial carcinoma and its relationship with clinical pathology[J].The Journal of Practical Medicine,2015,31(22):3717-3719.[孙丹,范余娟,徐红,等.子宫内膜癌中人类乳腺癌易感基因1微卫星不稳定性及其与临床病理的关系[J].实用医学杂志,2015,31(22):3717-3719.]
[8]Ye M,Sun DZ,Wei PK.The DNA microsatellite instability and gastric carcinoma[J].Chinese Journal of Clinicians(Electronic Edition),2013,(9):151-152.[叶敏,孙大志,魏品康.DNA微卫星不稳定与胃癌[J].中华临床医师杂志(电子版),2013,(9):151-152.]
[9]De MC,Forman D,Plummer M.Gastric cancer:epidemiology and risk factors[J].Gastroenterol Clin N,2013,107(3):230-236.
[10]Ahn HS,Kim SH,Kodera Y,et al.Gastric cancer staging with radiologic imaging modalities and UICC staging system[J].Dig Surg,2013,30(2):142-149.
[11]Teodoro JG,Parker AE,Zhu X,et al.p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolylhydroxylase.[J].Science,2006,313(5789):968-971.
[12]Alexandrov LB,Nikzainal S,Wedge DC,et al.Signatures of mutational processes in human cancer[J].Nature,2013,500(7463):415-21.
[13]Nan HM,Song YJ,Yun HY,et al.Effects of dietary intake and genetic factors on hypermethylation of the hMLH1gene promoter in gastric cancer.[J].World J Gastroenterol,2005,11(25):3834-3841.
[14]Tzanakis NE,Peros G,Karakitsos P,et al.Prognostic significance of p53 and Ki67 proteins expression in Greek gastric carcinoma patients[J].Acta Chir Belg,2009,109(5):606-611.
[15]Ohashi S,Okamura S,Urano F,et al.Clinicopathological variables associated with lymph node metastasis in submucosal invasive gastric carcinoma[J].Gastric Carcinoma,2007,10(4):241-250.
[16]Zhang JQ,Fu GZ,Wu HH,et al.Germline mutation analysis,microsatellite instability and clinical pathology in Hazakh in China hereditary nonpolyposis colorectal cancer pedigree[J].Chinese Journal of Experimental Surgery,2014,31(2):245-247.[张剑权,符国珍,吴海红,等.遗传性非息肉病性大肠癌微卫星不稳定临床病理和错配修复基因变异的研究[J].中华实验外科杂志,2014,31(2):245-247.]
[17]Ma Y,Tao Y.Research progress of MSI colorectal cancer[J].Practical Oncology Journal,2017,31(4):376-380.[马悦,陶冀.MSI结直肠癌的研究进展[J].实用肿瘤学杂志,2017,31(4):376-380.]
[18]Copija A,Waniczek D,Witko A,et al.Clinical significance and prognostic relevance of microsatellite instability in sporadic colorectal carcinoma patients[J].Int J Mol Sci,2017,18(1):107.
[19]Hernni-Eusébio J,Barbosa E.Phenotypic heterogeneity by germline mismatch repair gene defect in Lynch syndrome patients[J].Acta Med Port,2016,29(10):587-596.
[20]Palli D,Russo A,Ottini L,et al.Red meat,family history,and increased risk of gastric cancer with microsatellite instability.[J].Cancer Res,2001,61(14):5415-5419.
[21]Saridaki Z.Prognostic and predictive significance of MSIin stagesⅡ/Ⅲcolon carcer[J].World J Gastroenterol,2014,20(22):6809.