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 529 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 62 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed.

Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.47; 95% CI, 0.28-0.79; P <0.05), progression-free survival (PFS) (HR, 0.50; 95% CI, 0.35-0.72; P <0.05) and overall survival (OS) (HR, 0.48; 95% CI, 0.31-0.73; P <0.05) in endometrial cancers. HR mutation was related with clinical characteristics including FIGO stage (P<0.05), tumor grade (P<0.05) and histological types (P<0.05). HR mutation was enriched in MSI (hypermutated) group (49%) and copy-number low group (19.6%). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, the association between HR mutation and PFS was still significant (HR, 0.22; 95% CI, 0.05-0.88; P = 0.03), which indicating the HR mutation is an independent prognostic factor for PFS. Gene set enrichment analysis suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release.

Conclusion: 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

Citation Format: Luyang Zhao, Yibo Dai, Yuanjing Hu, Zhiqi Wang, Chengcheng Li, Guoqiang Wang, Jianliu Wang. Mutation in homologous recombination as a prognostic factor independent of TCGA molecular subtypes in endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 47.