Homologous Recombination Deficiency Is Associated with Shorter Survival in Colorectal Cancer Patients

Colorectal cancer (CRC) patients benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all patients. The remaining patients still lack effective therapeutic biomarkers to predict their prognosis.

We performed whole-exome sequencing (WES) to analyze 84 CRC specimens, classifying them into different groups based on their microsatellite status (MS), tumor mutation burden (TMB), homologous recombination deficiency (HRD) score, and clinicopathological features, which might be associated with clinical outcomes. Survival analysis and multivariable Cox regression modeling were employed to identify prognostic indicators. Comparative genomic profiling evaluated somatic mutations, copy number variations (CNVs), and pathway activation patterns across clinical subgroups.

The characteristics of the cohort (N = 84) revealed a median age of 52 years, with a male predominance (61.9%) and a majority of patients presenting with stage IV disease (77%). The HRD-high (HRD-H) subgroup accounted for 16.7%, while 19.0% of cases were microsatellite instability-high (MSI-H) and 22.6% were TMB-high (TMB-H). Multivariable analysis identified HRD-H as an independent predictor of overall survival (OS: HR = 0.19, 95% CI 0.12-0.94, p = 0.002). Comparative genomics demonstrated distinct mutation landscapes between HRD-H and HRD-low subgroups. In microsatellite-stable (MSS) patients, HRD-H status correlated with enriched SMAD4 mutations (p < 0.01) and differential activation of TGF-β/MYC signaling pathways compared to HRD-H-MSI counterparts.

HRD status serves as a novel independent prognostic biomarker in CRC. Our multi-parametric genomic framework delineates stratification-specific molecular signatures, advocating for HRD-integrated molecular diagnostics to optimize CRC management.