Molecular Classification And Clinicopathological Features Of Endometrial Carcinoma

Purpose of the study:Traditional histological classification and risk stratification can not accurately evaluate prognosis and guide treatment,resulting in clinical over-treatment and undertreatment.Therefore,more detailed and objective stratification of groups with high heterogeneity is of great significance for the accurate treatment of endometrial carcinoma.In the past decade,the molecular typing of endometrial carcinoma proposed by TCGA has changed our understanding of tumor classification,but the application of molecular typing in the clinical treatment of endometrial cancer still faces many problems to be solved.The purpose of this paper is to classify the patients with endometrial carcinoma according to the detection pathway recommended by consensus,to analyze the clinicopathological characteristics of each molecular classification,and to explore the clinical application of prognostic risk assessment based on the combination of clinicopathological factors and molecular typing.Methods:The clinical data of 76 patients with endometrial cancer diagnosed by standard operation in the first Bethune Hospital of Jilin University from February 2018 to February 2020 were collected.Mutations in the exonuclease domain of POLE gene were detected by multiple PCR,and mismatch repair（MMR）and p53 protein status were determined by immunohistochemistry.According to the commonly recommended molecular typing sequence,four subtypes were identified: POLE mutant（POLEmut）,mismatch repair deficiency（MMRd）,p53 protein abnormal（p53abn）and non-specific molecular profile（NSMP）.The relevant clinical data were collected and analyzed,and the follow-up deadline was April 30,2022.SPSS20 software was used for statistical analysis.The continuous variables in accordance with the normal distribution were expressed by the mean ±standard deviation,and the T test was used for inter-group comparison;the continuous variables that did not conform to the normal distribution were expressed by the median（quartile spacing）,and the Wilcoxon’s rank sum test was used for inter-group comparison.The counting data were expressed by frequency and constituent ratio,and chi-square test or Fisher accurate test were used for comparison between groups.Multivariate correlation analysis was carried out by binary Logistic regression model to test the level of aversion 0.05,and the difference was statistically significant when P < 0.05.The drawing is mainly drawn by Grapa Pad Prism8,and the flow chart is drawn by Edraw Max application.Results:1.Among the 76 patients with endometrial carcinoma,1 case（1.33%）had POLE pathogenic mutation and 27 cases had deletion of MMRd protein,of which 1 case was complicated with POLE pathogenic mutation.According to the consensus recommended molecular typing detection pathway of endometrial carcinoma,this case was divided into POLE mutant type,so there were 26 cases of MMRd type（34.21%）and 28 cases of abnormal expression of p53 protein,of which 10 cases were complicated with MMR protein deletion.Similarly,according to the molecular typing detection path recommended by consensus,the 10 cases were divided into MMRd type,so in this study,18 cases（23.68）were p53 abn type,and the other 31 cases（40.79）were NSMP type.2.The sequencing range of this study included all exons of POLE gene.22 cases of POLE gene mutations were detected in 76 patients,corresponding to 12 amino acid changes,of which 4 cases were located in the exon 9-14 region of POLE gene and 18 cases were outside the exonase region of POLE gene.According to the POLEScore score system,c.1366 G > C（p.A456P）score 6 was pathogenicity mutation,c.1282 G > A（p.A428T）,c.1394 C > T（p.A465V）and c.833 C > T（p.T278M）POLE-Score were all 3 points of ambiguous mutation.The pathogenicity of POLE exonuclease mutations was evaluated by In silico prediction tool,in which c.755 C > T（p.A252V）,c.A76G（p.T26A）,c.6053 G > A（p.S2018N）,c.6673 C > A（p R2225S）and c.2974 G > A（p.A992T）were non-pathogenic mutations,c.575 C > G（p.S192C）,c.6494 G > A（p.R2165H）and c.2140 G > C（p.E714Q）were ambiguous mutations.3.MMR protein deletion occurred in 27 of 76 patients with endometrial carcinoma in this study.There were 13 cases of single MMR protein deletion,including 3 cases of PMS2 deletion（11.11%）,8 cases of MSH6 deletion（29.63%）,1 case of MSH2 deletion（3.70%）,and 1 case of MLH1 deletion（3.70%）.There were 11 cases of double MMR deletion,including 7 cases of PMS2 and MLH1 deletion（25.93%）,4 cases of MSH6 and MSH2 deletion（14.81%）,2 cases of three MMR protein deletion（7.41%）,and 1 case of all four MMR protein deletion（3.70%）.4.There was no significant difference in basic clinical information such as age of onset,menopause,BMI,parity,complication,FIGO stage,mode of operation,adjuvant therapy and follow-up outcome among MMRd type,p53 abn type and NSMP type（P < 0.001）.5.In this study,the expression of Ki-67 in 76 patients with endometrial carcinoma,MMRd type,p53 ABN type,NSMP type,there was significant difference in the expression rate of Ki-67 among the three groups（Pos.001）.The expression rate of Ki-67 was consistent with the prognosis of each type.Among the 76 patients in this study,there was a significant difference in the positive expression rate of Vimentin among the three groups（P > 0.05）.The positive expression of Vimentin was also consistent with the prognosis of each type,but there was no significant difference in other pathological features of each type.6.In this study,the prognostic risk grades of 76 patients with endometrial carcinoma combined with molecular typing were as follows: low risk group 24 cases（31.58%）,medium risk group 24 cases（31.58%）,medium high risk group 11 cases（14.47%）,high risk group 15 cases（19.74%）.Late metastasis group 1 case（1.33%）.In the low-risk group,8 patients（33.33%）received adjuvant therapy with severe overtreatment,while a total of 10 patients（19.61%）in the other four groups were not treated.Conclusion:1.Except for POLE mutation,patients with NSMP endometrial carcinoma showed the best histopathological features,high differentiation,positive LVSI and lymph node metastasis.2.The proportion of endometrioid adenocarcinoma was the highest in patients with MMRd type endometrial carcinoma,mainly with high to moderate differentiation.The incidence of high risk pathological parameters such as positive LVSI and lymph node metastasis was between NSMP and p53 abn.3.Patients with p53 abn endometrial carcinoma showed the worst histopathological features,mainly poorly differentiated,and the incidence of high-risk pathological parameters such as positive LVSI and lymph node metastasis was higher than that of the other two groups.4.76 patients with endometrial carcinoma were divided into groups according to the prognostic risk of clinicopathological factors and molecular typing.It was found that there was no more accurate adjuvant therapy in patients with POLE mutant and MMRD.