Genomic profile of Chinese patients with endometrial carcinoma

Abstract Backgrounds Endometrial carcinoma (EC) is one of the most commonly diagnosed gynecologic malignancy in China. However, the genetic profile of Chinese EC patients has not been well established yet. Methods In current study, 158 Chinese EC patients were subjected to next-generation sequencing assay (74 took testing of EC-related 20-genes panel, and 84 took the expanded panel). Of the 158 patients, 91 patients were performed germline mutation testing using the expanded panel. Moreover, the public datasets from TCGA and MSKCC were utilized to compare the genomic differences between Chinese and Western EC patients. The proteomic and transcriptomic from CPTAC and TCGA were derived and performed unsupervised clustering to identify molecular subtypes. Results Among the 158 patients analyzed, a significant majority (85.4%) exihibited at least one somatic alteration, with the most prevalent alterations occurring in PTEN, PIK3CA, TP53, and ARID1A. These genomic alterations were mainly enriched in the PI3K, cell cycle, RAS/RAF/MAPK, Epigenetic modifiers/Chromatin remodelers, and DNA damage repair (DDR) signaling pathways. Additionally, we identified ten individuals (11.0%) with pathogenic or likely pathogenic germline alterations in seven genes, with the DDR pathway being predominantly involved. Compared to Western EC patients, Chinese EC patients displayed different prevalence in AKT1, MET, PMS2, PIK3R1, and CTCF. Notably, 69.6% of Chinese EC patients were identified with actionable alterations. In addition, we discovered novel molecular subtypes in ARID1A wild-type patients, characterized by an inferior prognosis, higher TP53 but fewer PTEN and PIK3CA alterations. Additionally, this subtype exhibited a significantly higher abundance of macrophages and activated dendritic cells. Conclusion Our study has contributed valuable insights into the unique germline and somatic genomic profiles of Chinese EC patients, enhancing our understanding of their biological characteristics and potential therapeutic avenues. Furthermore, we have highlighted the presence of molecular heterogeneity in ARID1A-wild type EC patients, shedding light on the complexity of this subgroup.