Expression Profiles And Clinicopathological Significance Of DNA Mismatch Repair (MMR) Protein In Prostate Cancer

According to the 2020 global cancer statistical report published by CA:a cancer journal for clinicians in 2021,prostate cancer is the most common malignant tumor in 112 countries.In 2020 alone,there are 1.4 million new cases and 375000 deaths in the world,and the mortality rate of male cancer is only second to that of lung cancer.In recent years,due to the gradual change of lifestyle,aging population and Prostate Specific Antigen(PSA)screening,the incidence rate of prostate cancer is increasing rapidly,and it is becoming a serious threat to the health of elderly men in China Compared with preoperative PSA level,tumor stage and surgical margin status,Gleason score is still the most important index to evaluate the invasion and prognosis of prostate cancer.In addition to the above-mentioned clinicopathological indicators,in the past two decades,researchers have made unremitting efforts to screen a series of molecular markers that can be used to help determine the prognosis,and initially formed some molecular pathological typing methods for prostate cancer.At present,the most famous molecular typing of prostate cancer is based on the Cancer Genome Atlas(TCGA)data,including ERG(46%),ETV1(8%),etv4(4%),FLI1(1%)gene fusion,spop(11%),FoxAl(3%)and IDH1(1%)gene mutation.In the early stage,our research group systematically discussed the gene changes that play a driving role in the malignant progression of prostate cancer in China,including ERG gene rearrangement,PTEN gene deletion,etc.,and proposed new molecular markers for the prognosis evaluation of prostate cancer,which provides an important basis for the establishment of molecular typing and clinical treatment of prostate cancer patientsMismatch repair(MMR)is an important DNA repair mechanism.Loss of MMR gene expression can lead to the accumulation of mismatch during DNA replication,leading to microsatellite instability(MSI).When MMR system is involved in DNA repair,it involves many mismatch repair proteins,including MutS(MSH2,MSH3 and MSH6)and MutL(MLH1,MLH3,PMS1 and PMS2).MLH1,MSH2,MSH6 and PMS2 are the dominant proteins of MMR.At present,more and more studies have shown that mismatch repair dysfunction is closely related to the occurrence and evolution of colorectal cancer,gastric cancer,pancreatic cancer,endometrial cancer,ovarian cancer and other malignant tumors.In clinic,MSI status and the expression of MLH1,MSH2,MSH6 and PMS2 have been used as important indicators for early screening of Lynch syndrome.In recent years,prostate cancer precise diagnosis and treatment strategy has benefited more and more patients.For example,the latest guidelines and consensus at home and abroad point out that patients with mismatch repair deficiency(dMMR)or high microsatellite instability(MSI-H)prostate are treated with PD-1 inhibitor pablizumab.There are two most commonly used methods to detect the absence of MMR expression:immunohistochemistry to detect the expression of MMR related proteins,and PCR to detect multiple microsatellite loci to determine the presence of MSI.At present,there are corresponding reports on the role of MMR in prostate cancer,but most of them are foreign studies.Most of them believe that the lack of MMR is closely related to poorly differentiated,aggressive and advanced prostate cancer(lymph node metastasis and distant metastasis).However,there is still a lack of systematic research on the expression and role of MMR in Chinese prostate cancer.In this study,we first collected 126 cases of radical resection of prostate cancer tissue samples from Qilu Hospital of Shandong University from 2013 to 2016,and made them into tissue microarray.We used immunohistochemistry to detect the expression of MMR protein in prostate cancer tissue samples.The negative rates of PMS2,MLH1,MSH2 and MSH6 were 33.3%,12.7%,14.3%and 21.4%respectively,and the strong positive rates were 17.5%,33.3%,61.9%and 36.5%respectively.Then,we analyzed the correlation between MMR expression status and clinicopathological characteristics of prostate cancer patients,such as age,preoperative PSA level,Gleason score,lymph node metastasis,distant metastasis and biochemical recurrence We found that the deletion of MLH1,MSH2 and MSH6 was associated with higher Gleason grade,and the deletion of MSH6 was associated with lymph node metastasis of prostate cancer.At the same time,we found a significant correlation between MSH2 and MSH6.In the follow-up study,we obtained the complete follow-up data of 118 patients with prostate cancer.Among them,19 patients had biochemical recurrence,and the biochemical recurrence rate was 16.1%.It should be noted that the proportion of biochemical recurrence was significantly higher in the cases with strong MLH1 expression(P<0.05).The deletion of MSH2 and MSH6 protein was associated with higher biochemical recurrence rate(P<0.05).Finally,we studied the relationship between molecular pathological features and molecular typing of prostate cancer.We used fluorescence in situ hybridization(FISH)to detect the rearrangement of ERG and the deletion of PTEN in prostate cancer samples.In 119 patients with prostate cancer,the incidence of ERG rearrangement was 13.4%(16/119);the deletion rate of PTEN was 10.7%(12/112),including 3.4%(4/119)loss of heterozygosity and 6.8%(8/119)loss of homozygosity.Our further analysis showed that the incidence of ERG rearrangement in patients with negative expression of MSH2 and MSH6 was 41.2%and 26.9%,which was significantly higher than that in patients with positive expression of MSH2 and/or MSH6.The incidence of PTEN deletion in patients with negative expression of MSH2 and MSH6 was also significantly higher,which was 35.3%and 22.7%.Therefore,this study suggests that the loss of MSH2 and MSH6 expression is accompanied by the rearrangement of ERG and the loss of PTEN Importantly,when we studied the samples with MSH2/MSH6/PTEN deletion separately,we found that the prostate cancer with MSH2/MSH6/PTEN deletion had higher malignancy and worse prognosis.Therefore,we believe that the patients with MSH2/MSH6/PTEN deletion may have higher clinical grade and worse prognosis,and have special clinical and molecular pathological characteristicsConclusion1.The loss rate of MMR protein expression in Chinese prostate cancer patients is similar to that in European and American countries.The loss of MLH1,MSH2 and MSH6 expression is associated with higher Gleason score,suggesting that the loss of MMR protein may be associated with the occurrence of higher grade prostate cancer.2.The overexpression of MSH2 and MSH6 was significantly associated with higher Gleason score,and the overexpression of MLH1 was associated with distant metastasis,so the overexpression of MMR was also associated with the pathological characteristics of prostate cancer.3.The deletion of MSH2 and MSH6 indicates a higher probability of biochemical recurrence in patients with prostate cancer,and they are significantly correlated with ERG rearrangement and PTEN deletion,which may play a role in the study of molecular mechanism and prognosis of prostate cancer.4.Patients with MSH2/MSH6/PTEN deletion may have higher clinical grade and worse prognosis,and have special clinical and molecular pathological characteristics.