A groundbreaking pan-cancer study published in BMC Cancer unveils the intricate landscape of homologous recombination deficiency (HRD) and homologous recombination repair (HRR) gene alterations across multiple solid tumor types within a vast Asian cohort. This extensive research, analyzing genomic and clinical profiles from 9,262 patients covering 17 solid cancers, provides unprecedented insight into the molecular mechanisms driving cancer progression and therapeutic vulnerabilities linked to DNA repair pathways.
At its core, homologous recombination deficiency (HRD) is understood as a pivotal factor determining sensitivity to platinum-based chemotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. These therapies have demonstrated particular efficacy in BRCA1 and BRCA2-mutated ovarian, breast, prostate, and pancreatic cancers due to their compromised ability to repair double-strand DNA breaks. This comprehensive study expands this understanding by exploring HRD and HRR alterations beyond these classical BRCA-associated cancers, redefining precision oncology strategies for diverse tumor types.
Utilizing the advanced OncoScreen™ Plus kit for detailed genomic sequencing and analysis, researchers quantitatively assessed HRD scores and biallelic loss in critical HRR genes alongside tumor suppressors. The HRD score—a composite measure reflecting genomic scars such as loss of heterozygosity (LOH), large-scale transitions (LST), and telomeric allelic imbalance (TAI)—served as a key biomarker for DNA repair deficiencies across tumor samples. This methodology enabled rigorous stratification of tumors based on their DNA repair proficiency and ensuing genomic instability.
One of the most striking findings was the significant variation of HRD scores between cancer types, each displaying a characteristic distribution with notable long-tail patterns signaling subgroups with highly elevated genomic instability. Approximately 21.3% of the analyzed tumors harbored pathogenic alterations in key HRR genes, emphasizing the widespread yet heterogeneous nature of HRD across solid malignancies. Additionally, 13.7% of the cohort exhibited HRD scores exceeding the clinically relevant threshold of 42, previously correlated with pronounced treatment sensitivity.
At the chromosomal level, events underpinning HRD—such as LOH, LST, and TAI—demonstrated shared features and distinct tumor-type specific patterns, hinting at the underlying biological complexity and tissue-specific routes through which homologous recombination repair is compromised. This nuanced chromosomal arm-level analysis underscores the necessity of precision and tumor-contextual interpretation of HRD biomarkers.
Delving deeper into gene-specific associations, biallelic loss—that is, the inactivation of both copies of a gene—proved critical in dictating elevated HRD scores. In classic BRCA-associated cancers, biallelic inactivation of genes like BRCA1, BRCA2, RAD51D, RAD51C, and PPP2R2A strongly correlated with heightened genomic instability. Conversely, in non-BRCA tumor types, losses involving BARD1, RAD51D, RAD54L, BRCA1, and MRE11 emerged as significant drivers of elevated HRD, suggesting alternative HRR pathway disruptions influencing tumor behavior across diverse histologies.
Intriguingly, alterations in TP53, a master tumor suppressor and guardian of genomic integrity, further accentuated HRD levels when present biallelically, regardless of coincident HRR gene changes. This observation points to a synergistic interplay where TP53 inactivation may exacerbate DNA repair deficiencies or enhance genomic instability through independent mechanisms, thereby amplifying tumor susceptibility profiles.
Clinical correlations revealed higher HRD scores predominantly in tumors characterized by advanced stage, older patient age, metastatic status, and PD-L1 positivity—features commonly associated with aggressive disease and immune evasion. Notably, samples lacking microsatellite instability-high (MSI-H) or POLE mutations, two distinct hypermutator phenotypes, showed stronger associations between HRD and structural chromosomal instability (SCIN), weighted genome instability index (WGII), and whole-genome doubling (WGD) events. These findings consolidate the emerging consensus that HRD manifests through multi-layered genomic aberrancies beyond point mutations alone.
Crucially, this study represents the largest pan-cancer evaluation of HRD within an Asian population to date, addressing a significant gap in genomic medicine where current knowledge has been predominantly derived from Western cohorts. By illuminating ethnic and demographic nuances in HRR gene alterations and their functional consequences, the research advocates for inclusive genomic studies critical for global precision oncology implementation.
The comprehensive nature of this analysis sets a new benchmark for HRD testing frameworks. It suggests that future diagnostic approaches should integrate multi-gene panels encompassing both canonical and non-canonical HRR players with chromosomal instability metrics to accurately stratify patients for targeted therapies. Such refined stratification is expected to enhance clinical decision-making, improve PARP inhibitor response prediction, and potentially guide novel combination treatments.
Moreover, the identification of cancer-specific HRD signatures at the chromosomal arm level opens avenues for biomarker development that capture tumor lineage and genomic context, optimizing personalized medicine beyond one-size-fits-all models. The novel associations observed between TP53 biallelic inactivation and HRD emphasize further research into synergistic genomic disruptions as therapeutic vulnerabilities.
In the realm of translational oncology, integrating these HRD insights with immune profiling, as evidenced by the linkage with PD-L1 positivity, hints at dual strategies that combine DNA repair-targeted agents and immunotherapies. Future clinical trials could explore such combinations, especially in patients exhibiting high genomic instability and immune checkpoint expression, to overcome resistance and improve outcomes.
This landmark study not only broadens the understanding of homologous recombination repair deficiencies and their genomic footprints but also underscores the heterogeneity inherent in DNA repair impairment across diverse solid tumors. The data lay a robust foundation for evolving HRD as a universal biomarker and for expanding the therapeutic utility of synthetic lethality beyond established BRCA-mutant contexts.
As precision oncology advances, such pan-cancer, multi-dimensional genetic analyses represent critical milestones in unraveling cancer’s molecular intricacies, with direct implications for tailored interventions, prognosis refinement, and ultimately, improved patient survival across global populations.
Subject of Research: Pan-cancer analysis of homologous recombination deficiency (HRD) and homologous recombination repair (HRR) gene alterations in solid tumors.
Article Title: Pan-cancer analysis of homologous recombination deficiency and homologous recombination repair–associated gene alterations in solid tumors from a large Asian cohort.
Article References:
Ren, L., Yao, R., Hou, T. et al. Pan-cancer analysis of homologous recombination deficiency and homologous recombination repair–associated gene alterations in solid tumors from a large Asian cohort. BMC Cancer 25, 946 (2025). https://doi.org/10.1186/s12885-025-14267-w
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14267-w
Tags: advanced genomic sequencing techniquesBRCA1 and BRCA2 mutationscancer therapeutic vulnerabilitiesDNA repair mechanismsgenomic profiling in cancerhomologous recombination deficiencyHRD and HRR gene alterationspan-cancer studyPARP inhibitors efficacyplatinum-based chemotherapy sensitivityprecision oncology strategiessolid tumor DNA repair pathways
