The Expression And Clinical Significance Of Mismatch Repair Protein In Colorectal Cancer

Background and ObjectiveColorectal cancer(CRC)is one of the common malignant tumors in the digestive system.The morbidity and mortality are the third and second place in global malignant tumors respectively.The path of occurrence is mainly chromosomal instability(CIN)pathway and microsatellite instability(MSI)pathway.MSI colorectal cancer is caused by DNA mutation,methylation or deletion of mismatch repair(MMR)gene,resulting in DNA mismatch repair defects,about 12%is associated with sporadic colorectal cancer,and about 3%is associated with Lynch syndrome.The expressions of four common mismatch repair proteins MLH1,MSH2,MSH6 and PMS2 in colorectal cancer,as well as the clinicopathological characteristics and clinical significance of microsatellite unstable CRC were analyzed to improve the understanding of this disease.MethodsA total of 310 CRC cases were collected from the first affiliated hospital of zhengzhou university from March 2016 to March 2017,which were surgically resected without preoperative diagnosis of chemoradiotherapy and had complete clinical data.Immunohistochemistry was used to detect the expression of four kinds of MMR proteins in CRC.MSI molecular detection and MMR gene mutation detection were performed in some cases.The relationship between clinicopathological features and deficient mismatch repair(dMMR)in colorectal cancer was analyzed retrospectively.Statistical analysis was performed using SPSS 17.0 software.The count data were tested byχ~2 or Fisher’s exact probability test.The difference between groups was tested byχ~2 test.The test level wasα=0.05,P<0.05 was considered statistically significant.Correlation analysis was performed using Spearman rank.Results1.Expression and correlation analysis of four MMR proteins in CRC.Among the 310 CRC cases,58 cases were dMMR cases,and the deletion rate was 18.7%.The expression deletion rates of MLH1,MSH2,MSH6 and PMS2 proteins were12.3%,2.3%,2.3%and 14.8%.Among 58 cases of dMMR,33 cases(56.9%)of MLH1 and PMS2 protein combined deletion,4 cases(6.9%)had a common deletion of MSH2 and MSH6.Spearman correlation analysis showed that MLH1 was significantly positively correlated with PMS2 expression(r_s=0.758,P<0.05),and there was a significant positive correlation between MSH2 and MSH6 protein expression(r_s=0.708,P<0.05).The MMR protein in CRC is often associated with deletion,and the combined deletion of MLH1 and PMS2 is dominant.2.The relationship between clinicopathological features of CRC patients with normal expression of MMR and dMMR.Immunohistochemical detection was performed in 310 cases of CRC.Among the 58 cases of dMMR CRC,26 cases(44.8%)were male and 32 cases(55.2%)were female.The mean age was 56(±14)years old,median age was 57 years old,33 cases(56.9%)were aged 60 years old.37cases(64.0%)with the maximum diameter of tumor 5cm.There were 30 cases(51.7%)of right colon,11 cases(19.0%)of left colon and 17 cases(29.3%)of rectum.One case was highly differentiated(1.7%),50 cases were moderately differentiated(74.1%),and 7 cases were poorly differentiated(24.2%).Mucinous adenocarcinoma or more extracellular mucus in 11 cases(19.0%).TNM stagingⅠ-Ⅱ37 cases(63.8%),Ⅲ-Ⅳperiod 21 cases(36.2%).Lymph node metastasis was found in 20 cases(34.5%),vascular thrombus in 22 cases(37.9%),and nerve invasion in 12 cases(20.7%).dMMR/MSI-H colorectal cancer was associated with location,degree of differentiation,histological type and nerve invasion(P<0.05),but not with gender,age,tumor size,angiocarcinoma thrombus,lymph node metastasis and TNM stage(P>0.05).3.The relationship between the expression of four MMR proteins and clinicopathological features.There was a statistical difference in MLH1 protein expression between the tumor sites(P<0.05).There were statistical differences in the expression of PMS2 protein between the size,location and differentiation degree of the tumor(P<0.05).There were statistically significant differences in MSH2 protein expression among the histological types of age,tumor site and differentiation degree(P<0.05).There were significant differences in the expression of MSH6 protein between the differentiation degree and histological type(P<0.05).4.Partial CRC MSI molecular detection and MMR gene detection.Of the 310cases of colorectal cancer,14 were tested for MSI,7 showed MSI-H,and 7 showed MSS.Sixteen patients underwent MMR gene mutation detection.The results showed that MMR gene germline mutations were observed in 4 cases,and MSI-H was found in 4 cases.The clinical data were found in 4 cases,and 4 cases had family history of colorectal cancer,which was diagnosed as Lynch syndrome.Conclusions1.In colorectal cancer,MMR protein is often associated with the deletion of MLH1 combined with PMS2,and MSH2 combined with MSH6.The deletion of MLH1 combined with PMS2 is the main one,while the deletion of MSH2/MSH6 is less than that of MLH1/PMS2.2.dMMR/MSI-H colorectal cancer often occurs in the right colon,with poor differentiation,often mucinous adenocarcinoma or more extracellular mucus,less neurological invasion.Patients with loss of MSH2 protein expression have a younger age of onset,and those with loss of PMS2 protein expression may have larger tumor size.3.The detection of MMR protein in colorectal cancer plays a role in screening Lynch syndrome.