Clinicpathologic Characteristics And Prognosis Of POLE Mutation And Other Related Gene Mutations In Endometrial Carcinoma

Objective:Searching the location of hotspot mutations in POLE mutant endometrial carcinoma,to explore the relationship between POLE hotspot mutations and other related gene mutations,discuss clinicopathological features and prognosis with different gene mutations and other clinical conditions,build a model to predict the prognosis of endometrial carcinoma.Methods:From December 2014 to March 2021,191 cancer histopathological samples were selected from patients who were first diagnosed as endometrial carcinoma by the Northern Theater Command General Hospital and who underwent total hysterectomy after diagnosis and curettage.Membrane cancer-related mutation gene chip and high-throughput sequencing,referring to TCGA,COSMIC and other databases and EC-related mutation genes in relevant literature,a total of 212 gene mutations were screened for detection(including POLE,PTEN,ARID1 A,PIK3CA,PIK3R1,ATM,BRCA2,CTCF,MSH2,TP53,ERBB2,etc.),the SNV/INDEL risk score was performed on the acquired data to exclude mutations of unknown significance(VUS),and statistics included POLE hotspot mutations(P286R、V411L、S297F、A456P、S459F、L424I、S297P、M444K、A465F)and the relationship between common gene mutations including non-hotspot mutations and the clinicopathological features of endometrial cancer,and explore the new pathogenic loci of POLE mutations.All patients in the cohort were followed up.They were divided into death group(n=23)and non-death group(n=168).Chi-square test and t-test were used to count common genes The impact of mutations and related clinicopathological features on overall survival(OS),select genes(TP53,ERBB2)and clinical indicators with a tendency to affect OS to be included in follow-up studies,and explore the prognosis of different mutation types of POLE genes and TP53,ERBB2 gene mutations Condition.Univariate and multivariate COX regression analysis was used to analyze the factors affecting the postoperative survival time of patients,and the Kaplan Meier survival curve was used to analyze the difference in survival time between different gene mutations and different clinical indications,and the prognosis prediction model was constructed and its value was evaluated.Results:Related mutations were detected in all 191 patients,and a total of 153 mutated genes were detected,including 76 cases of POLE mutations(39.79%,76/191);17 cases of POLE mutations had known hotspot mutations or pathogenic mutations(8.9%,17/191): 7 cases of V411 L,4 cases of P286 R,3 cases of S297 F,1 case of A456 P,1 case of M444 K,1 case of A465F;45 cases of VUS(30.89%,59/191),in which exonuclease domain mutation(EDM)(Exons exon9-14)3 cases:(1)one case of exon9 coding region was inserted into the second base of the intron immediately,but no amino acid changes were caused;(2)another case of exon11 coding region a base deletion occurred,resulting in a deletion between amino acids 366-369(366＿369del);(3)In the third case,the base G in the coding region of exon12 was replaced by A,resulting in the 376 th C The amino acid was replaced by threonine(A376T),and the base A in the exon13 coding region replaced the base G,causing the 411 th valine to be replaced by methionine(V411M).The results of SNV/INDEL risk scores predicted by each software showed that 366＿369del,A376 T,and V411 M were all pathogenic variants.In addition,except POLE the top 10 genes with mutation rate were PTEN,PIK3 CA,ARID1A,PIK3R1,CTCF,TP53,BRCA2,ATM,ERBB2,MSH2.Compared with the nondeath group,the death group was older,more prone to vascular invasion and lymph node metastasis,higher clinical stage,and more common TP53 and ERBB2 gene mutations(P<0.05).The results of COX regression analysis showed that older age,clinical stage III/IV,TP53 mutation,and ERBB2 mutation were independent risk factors for short survival after endometrial cancer surgery(P<0.05).There was no death outcome event in the POLE hotspot mutation group,but there was no statistically significant association with good prognosis(P<0.05),showing higher histological grade(FIGO grade 3)and less vascular invasion(P<0.05),had no significant correlation with age,tumor histological type,tumor size,depth of muscle invasion,lymph node metastasis,and clinical stage(P>0.05).The difference was not statistically significant.The EC prognosis prediction model was constructed based on age,clinical stage,TP53 mutation,and ERBB2 mutation.After testing,the model C-INDEX:0.849(95%CI: 0.762-0.936),with a good degree of discrimination,and the 3-year survival rate and 5 The calibration curves for annual survival all showed good agreement with good predictive power.Conclusions:The 366＿369del,A376 T,and V411 M mutations in the POLE exonuclease domain are new POLE pathogenic mutation sites in endometrial carcinoma.TP53 gene mutation,ERBB2 gene mutation,age,vascular invasion,lymph node metastasis,and clinical stage are risk factors for poor prognosis in patients with endometrial carcinoma.The prognosis prediction model of endometrial carcinoma constructed by age,clinical stage and TP53 and ERBB2 gene mutation status has good predictive ability and application value,and may provide a more accurate prognosis judgment for non-POLE hypermutated EC.