Integrating Pathology,Chromosomal Instability And Mutations For Risk Stratification In Early-stage Endometrioid Endometrial Carcinoma

Background: Risk stratifications for endometrial carcinoma(EC)depend on histopathology and molecular pathology.Histopathological risk stratification lacks reproducibility,neglects heterogeneity and contributes little to surgical procedures.Existing molecular stratification is useless in patient with specific pathological or molecular characteristics,and cannot guide postoperative adjuvant radiotherapies.Chromosomal instability(CIN),the numerical and structural alterations of chromosome resulting from ongoing errors of chromosome segregation,is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology,which may be applicable to the risk stratification of EC.Methods and Results: By analysis of CIN25 and CIN70,two reliable gene expression signatures for CIN,we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN.However,POLE-mutant,as a favorable prognostic factor,had elevated CIN signatures,and CTNNB1-mutant,as an unfavorable prognostic factor,had decreased CIN signatures.Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups.Integrating pathology,CIN signatures and POLE / CTNNB1 mutation stratified stageⅠendometrioid EC into four groups with improved risk prognostication and treatment recommendations.With database of gene dependence and cell biology experiment,we explored the effect of Fatostatin,which may effectively target endometrial cancer with serious CIN.Conclusions: We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC and the possibility of using Fatostatin.Our integrated risk model deserves for further improvement and Fatostatin need further validation.