Identification and Validation of a Novel Multiomics Signature for Prognosis and Immunotherapy Response of Endometrial Carcinoma.

Abstract

Purpose Cancer development and immune escape involve DNA methylation, copy number variation, and other molecular events. However, there are remarkably few studies integrating multiomics genetic profiles into endometrial cancer (EC). This study aimed to develop a multiomics signature for the prognosis and immunotherapy response of endometrial carcinoma. Methods The gene expression, somatic mutation, copy number alteration, and DNA methylation data of EC were analyzed from the UCSC Xena database. Then, a multiomics signature was constructed by a machine learning model, with the ROC curve comparing its prognostic power with traditional clinical features. Two computational strategies were utilized to estimate the signature's performance in predicting immunotherapy response in EC. Further validation focused on the most frequently mutant molecule, ARID1A, in the signature. The association of ARID1A with survival, MSI (Microsatellite-instability), immune checkpoints, TIL (tumor-infiltrating lymphocyte), and downstream immune pathways was explored. Results The signature consisted of 22 multiomics molecules, showing excellent prognostic performance in predicting the overall survival of patients with EC (AUC = 0.788). After stratifying patients into a high and low-risk group according to the signature's median value, low-risk patients displayed a greater possibility of respond to immunotherapy. Further validation on ARID1A suggested it could induce immune checkpoints upregulation, promote interferon response pathway, and interact with Treg (regulatory T cell) to facilitate immune activation in EC. Conclusion A novel multiomics prognostic signature of EC was identified and validated in this study, which could guide clinical management of EC and benefit personalized immunotherapy.