A Dual-Pathway Perspective on Synthetic Lethality and PARPi Sensitivity
Background: Esophageal squamous cell carcinoma(ESCC) remains a leading cause of cancer-related mortality. While angiogenesis and homologous recombination repair (HRR) deficiency involve two distinct oncogenic pathways, their interplay in ESCC remains poorly understood. In this study, multiomics data were integrated to characterize the dual pathway defined as VEGFC-high plus HRR deleterious mutation. Methods: We analyzed 63 ESCC cases from our retrospective cohort and 185 TCGA-ESCA samples. A composite HRR score was derived from RAD51 and gamma-H2AX immunohistochemistry. Whole-exome sequencing revealed mutations in 21 core HRR genes. TP53 was evaluated separately as a cooccurring mutation. Results: Core HRR mutations were detected in 16/63 (25.4%) patients, with BRCA2 (7.9%), ATM (6.3%), CHEK2 (3.2%), and PALB2 (3.2%) being the most frequent mutations. TP53 comutation occurred in 12 patients (19.0%). The HRR score demonstrated 100% sensitivity (16/16) and 68.1% specificity (32/47) for detecting WES-defined HRR mutations, with 76.2% concordance. The dual-pathway subgroup included 12 patients (19.0%), with significantly worse OS(HR 2.31, 95% CI 1.15–4.64; P=0.019) and PFS (HR 2.08, 95% CI 1.05–3.92; P=0.034). Both 95% CIs are entirely above 1.0. Conclusions: The VEGFC-HRR dual-pathway pathway defines a distinct ESCC subtype with aggressive clinical behavior and potential PARPi sensitivity. The WES+IHC dual-approach strategy provides a robust framework for patient selection.
Background: Esophageal squamous cell carcinoma(ESCC) remains a leading cause of cancer-related mortality. While angiogenesis and homologous recombination repair (HRR) deficiency involve two distinct oncogenic pathways, their interplay in ESCC remains poorly understood. In this study, multiomics data were integrated to characterize the dual pathway defined as VEGFC-high plus HRR deleterious mutation. Methods: We analyzed 63 ESCC cases from our retrospective cohort and 185 TCGA-ESCA samples. A composite HRR score was derived from RAD51 and gamma-H2AX immunohistochemistry. Whole-exome sequencing revealed mutations in 21 core HRR genes. TP53 was evaluated separately as a cooccurring mutation. Results: Core HRR mutations were detected in 16/63 (25.4%) patients, with BRCA2 (7.9%), ATM (6.3%), CHEK2 (3.2%), and PALB2 (3.2%) being the most frequent mutations. TP53 comutation occurred in 12 patients (19.0%). The HRR score demonstrated 100% sensitivity (16/16) and 68.1% specificity (32/47) for detecting WES-defined HRR mutations, with 76.2% concordance. The dual-pathway subgroup included 12 patients (19.0%), with significantly worse OS(HR 2.31, 95% CI 1.15–4.64; P=0.019) and PFS (HR 2.08, 95% CI 1.05–3.92; P=0.034). Both 95% CIs are entirely above 1.0. Conclusions: The VEGFC-HRR dual-pathway pathway defines a distinct ESCC subtype with aggressive clinical behavior and potential PARPi sensitivity. The WES+IHC dual-approach strategy provides a robust framework for patient selection.
shaoyongdong