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<p>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, <i>n</i> = 114), the Cancer Genome Atlas EC cohort (<i>n</i> = 500), and a high-grade serous ovarian cancer (HGSOC) cohort (<i>n</i> = 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%, <i>P</i> = 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%; <i>P</i> &lt; 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; <i>P</i> = 0.04) yet enhanced platinum sensitivity (HR 0.41, 95% CI 0.18–0.94; <i>P</i> = 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.</p>

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HRD in endometrial cancer: LST loss drives distinct genomic profile and platinum response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Ting Wan,
  • Qiaqia Li,
  • Wen Hao,
  • Ying Xie,
  • Binbin Chen,
  • Mufei Lin,
  • Die Dai,
  • Ziming Du,
  • Jundong Li,
  • Wei Wei

摘要

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.