The Clinical Application Of Mismatch Repair Protein In The Screening Of Lynch Syndrome Associated Endometrial Cancer

Purpose : The study analyzed the correlation between the expression loss of mismatch-repair protein and the clinicopathological characteristics in endometrial cancer,and combined with the personal or family history of lynch syndrome associated tumors and the PREMM5 model,discussion the application value of mismatch-repair protein expression in clinical screening of lynch syndrome associated endometrial cancer,so as to provide the theoretical basis for clincal screening strategies of lynch syndrome associated endometrial cancer.Methods : This study included a total of 192 patients diagnosed endometrial cancer in Yue Bei People’s Hospital from January 2018 to June 2020,collecting the clinicopathological data,such as age,body mass index,complications,personal and family history of tumor,PREMM5 score,tissue differentiation,FIGO stage,muscular invasion,lymphatictic metastasis,vascular infiltration and so on.The protein expression of mismatch repair genes was examined by immunohistochemistry in all tissue samples.T test,Chi-square test and Fisher exact test were used to analyze the correlation between the mismatch repair protein deficiency and the clinicopathological features.Thirteen Lynch syndrome-related genes were detected by next-generation sequencing in 34 patients with mismatch repair protein deletion or PREMM5 score ≥2.5%.Combined with the results of germline gene testing,we analyzed and evaluated the advantages and disadvantages of several screening strategies,including immunohistochemistry,personal and family tumor history and PREMM5.Results: Among the 192 patients who underwent mismatch repair protein immunohistochemical detection,54 patients(28.1%)had at least one mismatch-repair protein expression deletion,among which MLH1 combined with PMS2 protein expression loss accounted for the largest proportion(59.3%).The deletion rate of mismatch-repair protein in patients with positive family history of cancer was higher than that in patients with negative family history of cancer(80.0%vs.25.3%,p<0.05).There was no significant difference in the expression loss rate of mismatch repair protein among the clinical features such as body mass index,complications and pathological features such as tissue type,tissue differentiation degree,FIGOstage,muscular invasion and vascular invasion(p >0.05).The loss rate of MSH6 was significantly higher in non-overweight patients(BMI<24 kg/m2)than that in overweight patients(11.3%vs.1.8%,p=0.009).The loss rate of MSH6 was higher in patients with the personal or family history of LS-associated cancer than that in those without(16.7%vs.4.6%,p=0.036).There was no significant difference in the expression loss of MLH1,PMS2,MSH2 and MSH6 between the age ≤55 years old and the >55 years old group,between the diabetes mellitus group and the hypertension group(p>0.05).The loss rate of PMS2 in G3 group was significantly higher than that in G1 group(33.3%vs.11.8%,p=0.041).There were no significant differences in the expression loss of MLH1,PMS2,MSH2 and MSH6 among different pathological types,invasion of deep muscle layer(≥1/2),vascular invasion,lymphatic metastasis,and FIgo score period(p > 0.05).Of the 34 patients who underwent lynch syndrome associated germline gene testing,11 patients had mutations;MSH6 mutation was occurred in 4 patients,PMS2 or MUYTH mutation were occurred in each 2 patients,and MLH1,MSH2 or MLH3 mutation were occurred in each 1 patients.Six patients with pathogenic mutations and suspected pathogenic mutations were diagnosed with LS-EC,and the positive rate of personal and family history in the LS-EC group was higher than that in the sporadic endometrial cancer group(66.7%vs.17.9%,p=0.031).The expression of mismatch repair protein was lost in all six LS-EC patients,and the sensitivity of IHC method reached 100%.PREMM5 score of all six patients was≥2.5%,and the sensitivity was 100%.Of the six patients,four patients had the personal or family history of LS-associated cancer,with a sensitivity of 66.67% and specificity of 82.14%.Conclusions: In this study the most common type of mismatch repair protein deletion in endometrial cancer was MLH1 combined with PMS2 protein deletion;the MSH6 gene had the highest mutation rate,and the MSH6 protein deletion was associated with the personal or family history of LS-related malignancies;Immunohistochemical examination of mismatch repair genes combined with the personal and family history of Lynch syndrome associated endometrial cancer may be an important primary screening tool for Lynch syndrome.