Optimized molecular classification of endometrial carcinoma-based on the combination of POLE mutations with homologous recombination deficiency (HRD).
Authors: Gao Min , Wang Wei , Song Nan , Li Qian , Zheng Hong , Gao Weijiao , Zhang Naiyi , Shu Tong , Zhang Nan , Wang Hongguo , Gao Yunong 
Published: June 2022

e17628 Background: Molecular analysis of endometrial carcinoma (EC) has identified four clinically significant molecular subgroups with different prognoses: POLE mutations, microsatellite instability-high (MSI-H/dMMR), copy number low (CN-L/p53-normal), and copy number high (CN-H/p53-aberrant). However, the convenience and repeatability of detection methods for molecular classification, as well as the evaluation of their prognostic significance, need to be further explored. Recently, homologous recombination deficiency (HRD) has been studied to show the prognostic value in EC. Here, we aimed to establish a next-generation sequencing (NGS)-based one-stop method with the combination of HRD and POLE mutations for molecular classification of EC. Methods: Paraffin-embedded tissues of 143 eligible EC patients were collected from Beijing Cancer Hospital between 2011 and 2020 and sequenced using a panel of 520 cancer-related genes which could also detect MSI status (OncoScreen Plus, Burning Rock Biotech). HRD score was calculated as the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores based on the sequencing data. Results: The median follow-up time in this cohort was 38.77 months. We firstly classified EC patients into four subgroups: POLE mutations (mut) (n = 9, 6.3%), MSI-H (n = 45, 31.5%), TP53 wildtype (wt) (n = 67, 46.9%), and TP53 mut (n = 22, 15.4%). POLE mut subgroup had the excellent prognosis as no patient in this subgroup relapsed after surgical resection. Compared with TP53 mut subgroup, the other two subgroups had better prognosis [disease free survival (DFS): TP53 wt: hazard ratio (HR), 0.2, 95% CI, 0.07-0.57, P = 0.003; MSI-H: HR, 0.2, 95% CI, 0.06-0.68, P = 0.01; overall survival (OS): TP53 wt: HR; 0.11, 95% CI, 0.02-0.56, P = 0.008; MSI-H: HR, 0.25, 95% CI, 0.06-1.03, P = 0.055]. Except for the patients with POLE mut, the others were then further optimized and divided into two groups based on HRD score with the cutoff of 13: HRD-high (n = 15, 11.5%) and HRD-low (n = 116, 88.5%). Patients in HRD-low subgroup showed much improved survival than those in HRD-high subgroup (DFS: HR, 0.06, 95% CI, 0.02-0.15, P < 0.001; OS: HR, 0.06, 95% CI, 0.02-0.21, P < 0.001). Most notably, the postoperative recurrence rate was 36.4% in the TP53 mut subgroup with the worst prognosis in the traditional classification, and 66.7% in the HRD-high subgroup with the worst prognosis in the optimized classification. Conclusions: The method of classifying EC patients into four subgroups by NGS large panel provides similar clinical features to previous reports classified by other methods but is more convenient and stable. Furthermore, the method of combination of POLE mutations with HRD offers more accurate disease risk stratification and demonstrates the potential for directing therapy for EC patients.