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

Background and objectiveAmong all malignant tumors,the morbidity of colorectal cancer(CRC)ranks third in both men and women in the world,and is a major disease affecting public health.Colorectal cancer has a high degree of heterogeneity at the genetic and molecular level,the occurrence process is complex,and the development process is slow,which is a multi-step biological process.Microsatellite instability(MSI)is the second leading cause of colorectal cancer,and about 15%of colorectal cancer occur through this pathway.The occurrence of MSI is mainly due to the functional defects of mismatch repair caused by structural mutation,methylation or deletion of mismatch repair genes.The absence of this system weakens the DNA repair mechanism,accelerates the accumulation of potential mutations,and the error rate in the replication process can be increased to 100-1000 times.Defects in the MMR system are associated with increased susceptibility to certain types of cancer,especially colorectal cancer.Microsatellite instability-high(MSI-H)colorectal cancer has different clinical and pathological features from microsatellite stability(MSS)/microsatellite instability-low(MSI-L)colorectal cancer,and there are differences in diagnosis,treatment and prognosis.Although the overall survival rate of colorectal cancer has improved in recent years,the cornerstone of the treatment of metastatic colorectal cancer is chemotherapy(fluorouracil plus oxaliplatin or irinotecan)combining with molecular therapy.However,the treatment of people with re-progression after first-line and second-line treatment is faced with many challenges.In recent years,the field of immunotherapy has made rapid development,which puts forward a new idea for the treatment of metastatic colorectal cancer.However,not all colorectal cancers produce a high degree of inflammation.Immune checkpoint inhibitors have been shown to be beneficial to patients with mismatch repair loss of deficient mismatch repair(dMMR)or MSI-H metastatic colorectal cancer,but have no effect on proficient mismatch repair(pMMR)colorectal cancer.Therefore,accurate molecular phenotypic classification of colorectal cancer patients is of great value to the individual prognosis and treatment of colorectal cancer.At present,immunohistochemical MMR detection has become a first-line screening method for microsatellite status of colorectal cancer.In this study,immunohistochemical method was used to analyze the correlation between the expression of MMR protein and the clinicopathological characteristics of patients with colorectal cancer,and to explore the guiding significance of MMR detection for treatment and prognosis,so as to provide a basis for clinical diagnosis and treatment of colorectal cancer.Method1.The clinical and pathological data of 162 patients with colorectal cancer who received surgical treatment in Subei People's Hospital from June 2019 to March 2020 were selected and collected.The inclusion criteria of the patients were as follows:(1)colorectal cancer confirmed by histologypathology;(2)no preoperative anti-tumor therapy,including radiotherapy and chemotherapy,immunotherapy,etc.;(3)radical resection or palliative surgery;(4)clinical and pathological data available for analysis.The exclusion criteria were as follows:(1)appendiceal and anal tumors;(2)colorectal metastases;(3)squamous cell carcinoma,melanoma and gastrointestinal stromal tumors;(4)carcinoma in situ(high-grade intraepithelial neoplasia);(5)diagnosed or considered as hereditary adenomatous polyposis and HNPCC.2.The expression of MLH1?MSH2?MSH6?PMS2 in CRC was detected by immunohistochemical method.When the four mismatch repair proteins are all expressed,the mismatch repair function can be judged to be pMMR;if one or more of the four proteins are not expressed,it will be judged as dMMR.Retrospective analysis of the correlation between clinicopathological features and dMMR in colorectal cancer.3.Statistical analysis was performed using SPSS 20.0 software.Between groups,Chi-square test was used for univariate analysis of differences between groups,and Logistic regression analysis was used for multivariate analysis,Spearman rank correlation analysis was used to analyze the correlation.Results1.Expression of MMR protein in colorectal cancer:of the 162colorectal cancer cases,62 had dMMR,the deletion rate is 38.3%.The deletion rates of MLH1,MSH2,MSH6 and PMS2 were 16.7%,2.5%,1.9%and 34.6%respectively.The combined deletion rate of MLH1-PMS2 was 14.8%and the combined deletion rate of MSH2-MSH6 was 1.2%.The combined deletion rate of MSH1-MSH2 and MSH2-PMS2 were both 1.2%.Spearman rank analysis showed that there was a significant correlation between MLH1 and PMS2 expression(rs=0.511,P=0.000),and a significant correlation between MSH2 and MSH6 expression(rs=0.568,P=0.000).The combined deletion of MMR protein is often seen,the combined deletion of MLH1-PMS2 is the most common.2.dMMR CRC group and pMMR CRC group have significant difference in tumor location,tumor diameter and tumor cell differentiation(P<0.05),and no significant difference in gender,age of onset,degree of invasion,lymph node metastasis,distant metastasis,TNM stage(P>0.05);Subgroup analysis showed that the expression of MLH1 protein was correlated with tumor diameter(P<0.05),and the expression of PMS2 protein was related to tumor location,tumor diameter and tumor cell differentiation(P<0.05).Multivariate analysis showed that dMMR was closely related to tumor location,tumor diameter and tumor cell differentiation.Conclusion1.Compared with pMMR CRC,dMMR CRC accounts for a lower overall proportion of colorectal cancer;MLH1 and PMS2 deletions are more common among the four MMR proteins;Combind deletions of MMR proteins often occur in colorectal cancer,the combind deletion of MLH1-PMS2 is the most common.2.dMMR CRC has clinicopathological features different from pMMR CRC.dMMR/MSI-H colorectal cancer usually occur in patients with large diameter,low differentiation of tumor cells,tumor located in the right colon.MLH1 deletion usually occur in patients with large tumor diameter,while PMS2 deletion occur in patients with large tumor diameter,low differentiation of tumor cells,tumor located in the right colon.