湖南地区结直肠癌中错配修复蛋白MSH2、MSH6、MLH1及PMS2的表达与临床病理特征的关系
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摘要
目的:探讨错配修复蛋白MSH2、MSH6、MLH1及PMS2在结直肠癌(Colorectal cancer,CRC)组织中的表达及其临床病理意义。方法:应用免疫组化PV法检测结直肠癌组织(191例)中MSH2、MSH6、MLH1及PMS2的表达情况,将4种MMR蛋白中的1种及以上表达缺失判定为错配修复基因缺陷(dMMR),全部阳性判定为错配修复基因完整(pMMR),并分析其与临床病理特征的关系。结果:(1)191例中pMMR组159例,MMR蛋白表达率83.2%,dMMR组32例,MMR蛋白缺失率为16.8%。MSH2、MSH6、MLH1及PMS2的表达缺失率分别为2.6%、2.6%、8.9%及14.7%;其中共同缺失表达类型为MSH2-MSH6、MLH1-PMS2及4种共同缺失者分别为4例(2.1%)、14例(7.3%)、2例(1.0%)。(2)CRC癌患者dMMR与pMMR在肿瘤部位、肿瘤直径、分化程度等临床病理特征方面比较,差异均有统计学意义(P<0.05),而在性别、年龄、浸润深度、淋巴结转移、脉管侵犯和神经侵犯等方面比较,差异均无统计学意义(P>0.05)。结论:MMR蛋白与CRC临床病理特征关系密切。MMR蛋白对预测CRC的恶性程度、临床预后及发病机制方面可能有指导意义。
Objective:To investigate the expression of mismatch repair protein( MLH1,MSH2,MSH6 and PMS2)with clinicopathological features in colorectal cancer.Method:The expression of mismatch repair protein MLH1,MSH2,MSH6 and PMS2 were determined by immumohistochemistry in 191 cases of CRC.Deletion of one or more of the four MMR proteins were identified as mismatch repair gene defects(dMMR),and all positives were mismatch repair gene integrity(pMMR),their relationship with clinicopathological features was analyzed.Result:Negative staining of MMR proteins was found in 32 cases analyzed.The frequency of loss expression in MSH2,MSH6,MLH1 and PMS2 was 2.6%,2.6%,8.9% and 14.7% respectively.Among them,double proteins absence were found in MSH2/MSH6 in 4 cases(2.1%)and MLH1/PMS2 in 14 cases(7.3%).There 2 cases(1.0%)with 4 protein deletion.Patients with dMMR and pMMR in CRC had difference in tumor location,tumor diameter and degree of differentiation(P<0.05),but had no obvious difference in gender,age,invasion depth,lymph node metastasis,vascular invasion and neurological invasion(P>0.05).Conclusion:There is a close relationship between MMR proteins and the clinicopathological characteristics of colorectal cancer.MMR proteins may be biological indicators for estimating malignant degree,clinical prognosis and pathogenesis mechanism of CRC.
Objective:To investigate the expression of mismatch repair protein( MLH1,MSH2,MSH6 and PMS2)with clinicopathological features in colorectal cancer.Method:The expression of mismatch repair protein MLH1,MSH2,MSH6 and PMS2 were determined by immumohistochemistry in 191 cases of CRC.Deletion of one or more of the four MMR proteins were identified as mismatch repair gene defects(dMMR),and all positives were mismatch repair gene integrity(pMMR),their relationship with clinicopathological features was analyzed.Result:Negative staining of MMR proteins was found in 32 cases analyzed.The frequency of loss expression in MSH2,MSH6,MLH1 and PMS2 was 2.6%,2.6%,8.9% and 14.7% respectively.Among them,double proteins absence were found in MSH2/MSH6 in 4 cases(2.1%)and MLH1/PMS2 in 14 cases(7.3%).There 2 cases(1.0%)with 4 protein deletion.Patients with dMMR and pMMR in CRC had difference in tumor location,tumor diameter and degree of differentiation(P<0.05),but had no obvious difference in gender,age,invasion depth,lymph node metastasis,vascular invasion and neurological invasion(P>0.05).Conclusion:There is a close relationship between MMR proteins and the clinicopathological characteristics of colorectal cancer.MMR proteins may be biological indicators for estimating malignant degree,clinical prognosis and pathogenesis mechanism of CRC.
引文
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[15]Amira A T,Mouna T,Ahlem B,et al.Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability[J].Tumour Biol,2014,35(7):6283-6291.
[16]晋龙,眭玉霞,王丽萍,等.结直肠癌错配修复蛋白MLH1、MSH2、MSH6及PMS2表达与临床病理特征的关系[J].诊断病理学杂志,2017,24(11):813-817.
[17]Rodriges Blanko E,Kadyrova L Y,Kadyrov F A.DNAMismatch Repair Interacts with CAF-1-and ASF1A-H3-H4-dependent Histone(H3-H4)2 Tetramer Deposition[J].J Biol Chem,2016,291(17):9203-9217.
[18]顾晋,汪建平.中国结直肠癌诊疗规范(2017年版)[J/OL].中华临床医师杂志(电子版),2018,12(1):1089-1103.
[19]于静,张晓莹,赵峰,等.新疆维吾尔族及汉族散发性结直肠癌中hMLH-1、hM-SH-2差异性表达及临床意义[J].临床与实验病理学杂志,2015,31(10):1085-1088,1094.
[20]Buchanan D D,Rosty C,Clendenning M,et al.Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency(suspected Lynch syndrome)[J].Appl Clin Genet,2014,7:183-193.
[2]Miao Z,Deng X,Shuai P,et al.Upregulation of SOX18 in colorectal cancer cells promotes proliferation and correlates with colorectal cancer risk[J].Onco Targets Ther,2018,11:8481-8490.
[3]Sameer A S,Nissar S,Fatima K.Mismatch repair pathway:molecules,functions,and role in colorectal carcinogenesis[J].Eur J Cancer Prev,2014,23(4):246-257.
[4]Yang J,Xiao J,Feng J,et al.One-year Unplanned Readmission After Colorectal Cancer Surgery in Western China[J].J Invest Surg,2018:1-5.
[5]Fang Y,Liang X,Xu J,et al.miR-424 targets AKT3 and PSAT1 and has a tumor-suppressive role in human colorectal cancer[J].Cancer Manag Res,2018,10:6537-6547.
[6]Roberts M E,Jackson S A,Susswein L R,et al.MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer[J].Genet Med,2018,20(10):1167-1174.
[7]晋薇,马亚琪,王昀,等.错配修复基因MLH1、MSH2、MSH6及PMS2在子宫内膜癌中的表达及临床意义[J].诊断病理学杂志,2018,25(5):335-339.
[8]Wang W,He Y,Rui J,et al.miR-410 acts as an oncogene in colorectal cancer cells by targeting dickkopf-related protein 1 via the Wnt/β-catenin signaling pathway[J].Oncol Lett,2019,17(1):807-814.
[9]Niu W,Wang G,Feng J,et al.Correlation between microsatellite instability and RAS gene mutation and stageⅢcolorectal cancer[J].Oncol Lett,2019,17(1):332-338.
[10]Behrouz Sharif S,Hashemzadeh S,Mousavi Ardehaie R,et al.Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker[J].Oncol Lett,2016,12(6):5335-5343.
[11]Nouri Nojadeh J,Hashemzadeh S,Samadi Kafil H,et al.Evaluation of microsatellite instability in tumor and tumor marginal samples of sporadic colorectal cancer using mononucleotide markers[J].EXCLI J,2018,17:945-951.
[12]徐晋珩,刘丽云,田莉,等.散发性结直肠癌癌组织中错配修复蛋白和nm23蛋白表达与临床病理特征的关系[J].东南大学学报(医学版),2018,37(4):642-648.
[13]Park J H,Powell A G,Roxburgh C S,et al.Mismatch repair status in patients with primary operable colorectal cancer:associations with the local and systemic tumour environment[J].Br J Cancer,2016,114(5):562-570.
[14]Flores-Rozas H,Jaafar L,Xia L.The Role of DNA Mismatch Repair and Recombination in the Processing of DNA Alkylating Damage in Living Yeast Cells[J].Adv Biosci Biotechnol,2015,6(6):408-418.
[15]Amira A T,Mouna T,Ahlem B,et al.Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability[J].Tumour Biol,2014,35(7):6283-6291.
[16]晋龙,眭玉霞,王丽萍,等.结直肠癌错配修复蛋白MLH1、MSH2、MSH6及PMS2表达与临床病理特征的关系[J].诊断病理学杂志,2017,24(11):813-817.
[17]Rodriges Blanko E,Kadyrova L Y,Kadyrov F A.DNAMismatch Repair Interacts with CAF-1-and ASF1A-H3-H4-dependent Histone(H3-H4)2 Tetramer Deposition[J].J Biol Chem,2016,291(17):9203-9217.
[18]顾晋,汪建平.中国结直肠癌诊疗规范(2017年版)[J/OL].中华临床医师杂志(电子版),2018,12(1):1089-1103.
[19]于静,张晓莹,赵峰,等.新疆维吾尔族及汉族散发性结直肠癌中hMLH-1、hM-SH-2差异性表达及临床意义[J].临床与实验病理学杂志,2015,31(10):1085-1088,1094.
[20]Buchanan D D,Rosty C,Clendenning M,et al.Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency(suspected Lynch syndrome)[J].Appl Clin Genet,2014,7:183-193.