Abstract
While homologous recombination deficiency (HRD) presents therapeutic opportunities in endometrial cancer (EC), its molecular determinants and clinical implications remain poorly characterized. Through genomic analysis of 688 cancer-related genes combined with genomic scar assessment, we investigated HRD molecular features and clinical relevance of HRD across three cohorts: an EC cohort from Sun Yat-sen University Cancer Center (SYSUCC, n = 114), the Cancer Genome Atlas EC cohort (n = 500), and a high-grade serous ovarian cancer (HGSOC) cohort (n = 118). HRD was identified in 23.7% of SYSUCC EC cases, and HRD tumors paradoxically had fewer short-nucleotide variations in HRR genes than proficient (HRP) tumors (18.52% vs. 48.28%, P = 0.007). Mechanistic analysis revealed large-scale transition (LST) losses as the potential predominant HRD driver in EC, occurring significantly more frequently in HRD versus HRP tumors (74.1% vs 5.7%; P < 0.001). Comparative genomics demonstrated enrichment of HRR gene LST losses was EC-specific, contrasting with HGSOC where LST distribution was HRD-independent. Clinically, elevated HRD scores predicted reduced progression-free survival (HR 1.74, 95% CI 1.03-2.94; P = 0.04) yet enhanced platinum sensitivity (HR 0.41, 95% CI 0.18–0.94; P = 0.034). Our findings indicate that the HRD phenotype in EC, driven primarily by LST losses rather than short-nucleotide variations, serves as both a prognostic and predictive biomarker.
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Data availability
Human DNA data of the TCGA cohort (EC) are available via UCSC XENA (cohort name: UCEC; dataset name: MuTect2 Variant Aggregation and Masking; https://xenabrowser.net/datapages/) for interactive use. The HRD scores of the TCGA cohort (EC) analyzed during this study are included in ref. 35 and its supplementary information files. The data of the SYSUCC cohort are not publicly available but are available from the corresponding author on reasonable request. The data of the FUDAN cohort have been deposited into the CNGB Sequence Archive(CNSA) of China National GeneBank DataBase (CNGBdb) with accession numberCNP0001456.
Code availability
The underlying code for this study is not publicly available but may be made available to qualified researchers on reasonable request from the corresponding author.
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Acknowledgements
The authors thank the participants and staff of the Sun Yat-sen University Cancer Center for their contributions. The research reported in this manuscript was supported by Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515111160) to W.W., co-funding by the National Natural Science Foundation of China (No. 82203753) and Guangzhou Science and Technology Program (Grant No. 2023A04J1784) to Q.L.
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W.W., Z.M.D., and L.J.D.: conceptualization, methodology, draft polish. W.T. and Q.Q.L.: provided clinical samples and data collection. H.W.: provided data of the FUDAN cohort. Y.X.: analyzed data. M.F.L., B.B.L., and D.D.: writing-original draft. All the authors have read and approved the final manuscript.
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Wan, T., Li, Q., Hao, W. et al. HRD in endometrial cancer: LST loss drives distinct genomic profile and platinum response. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01347-8
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DOI: https://doi.org/10.1038/s41698-026-01347-8
