Journal: NPJ precision oncology
This study characterizes homologous recombination deficiency (HRD) in endometrial cancer (EC) using targeted sequencing of 688 cancer-related genes plus genomic scar analysis across three cohorts: a SYSUCC EC cohort (n=114), TCGA EC cohort (n=500), and a high-grade serous ovarian cancer (HGSOC) cohort (n=118).
Key findings:
- Prevalence and mutation pattern of HRD in EC
- • HRD was present in about one-quarter of EC cases in the SYSUCC cohort (23.7%).
- • HRD tumors unexpectedly had fewer short-nucleotide variants in homologous recombination repair (HRR) genes than homologous recombination–proficient (HRP) tumors (18.5% vs 48.3%; P=0.007), indicating that classic HRR point mutations are not the main driver of HRD in EC.
- Genomic mechanism: LST-driven HRD
- • Large-scale transition (LST) losses were identified as the predominant genomic feature underlying HRD in EC.
- • LST losses were far more frequent in HRD versus HRP EC tumors (74.1% vs 5.7%; P<0.001).
- • Enrichment of LST losses in HRR genes was specific to EC; in HGSOC, LST distribution did not differ by HRD status, highlighting a tissue-specific pattern of HRD biology.
- Clinical implications
- • Higher HRD scores were associated with worse progression-free survival (HR 1.74; 95% CI 1.03–2.94; P=0.04), supporting HRD as an adverse prognostic marker in EC.
- • Conversely, elevated HRD scores predicted greater platinum sensitivity (HR for progression with platinum 0.41; 95% CI 0.18–0.94; P=0.034), indicating HRD as a positive predictive biomarker for platinum-based chemotherapy benefit.
Overall, the work shows that in endometrial cancer, HRD is relatively common and is driven mainly by structural genomic alterations (LST losses) rather than point mutations in HRR genes, with HRD scores carrying both prognostic and predictive value—particularly for platinum responsiveness.