Mutation in homologous recombination to predict a better prognosis in endometrial cancer.

Abstract

6082 Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 48 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed.Gene set enrichment analysis (GSEA) were used to invesgate the gene signaling. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.39; 95% CI, 0.22-0.71; P = 0.002), progression-free survival (PFS) (HR, 0.46; 95% CI, 0.31-0.68; P < 0.001) and overall survival (OS) (HR, 0.45; 95% CI, 0.28-0.72; P = 0.001) in endometrial cancers. HR mutation was related with clinical characteristics including histological types (P < 0.05). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, TP53 mutation, POLE mutation, the association between HR mutation and PFS was still significant (HR, 0.48; 95% CI, 0.27-0.86; P < 0.05), which indicating the HR mutation is an independent prognostic factor for PFS. HR mutations were associated with a higher tumor mutation burden. GSEA suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. In MSS endometrial cancers, HR mutation still showed a longer PFS (HR, 0.57; 95% CI, 0.34-0.98; P = 0.04), suggested HR mutation may help predict the effect of immunotherapy in MSS endometrial carcinoma. Conclusions: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications and provides an inspiration for screening patients who may benefit from ICBs in endometrial cancer in the future.