Multi-omics analysis of high-grade serous ovarian cancers reveals heterogeneity and distinct immunological patterns based upon clinico-genomic status.

Abstract

High-grade serous ovarian cancer (HGSOC) is characterized by remarkable intratumoral heterogeneity and variable tissue architectures, dictating differential therapeutic responses. Although BRCA1/2 mutations correlate with improved responses to DNA-damaging agents, how BRCA genotype shapes the tumor immune microenvironment (TIME) remains incompletely understood. Here, we integrated whole exome sequencing, total RNA sequencing and spatial transcriptomics to profile a cohort of BRCA-mutated (BRCA-MT) and non-BRCA-mutated (BRCA-WT) HGSOC tumors. While bulk transcriptomics highlighted global phenotypic shifts, suggesting a more pro-inflammatory milieu in BRCA-MT tumors, spatially resolved analysis revealed how these differences manifest within specific tissue architectures. Integrated clustering revealed recurrent spatial transcriptional states across genotypes. Specifically, we identified a transcriptionally distinct immune-enriched region (IC7) characterized by low tumor purity, interferon signaling, and antigen-presentation programs. Reference-based RCTD deconvolution provided orthogonal computational support that IC7 was enriched for T/NK and dendritic cells relative to non-IC7 regions. At the patient level, the functional state of IC7 was highly BRCA-dependent: BRCA-MT tumors exhibited stronger enrichment of interferon-α/γ responses and inflammatory signaling than BRCA-WT tumors. Exploratory CellChat analysis further suggested genotype-associated differences in predicted immune-related signaling. We also identify a conserved structural interface between CAF-like region (IC3) and macrophage-rich region (IC4), accompanied by a predicted CXCL12-CXCR4 chemokine recruitment axis. Taken together, these findings support a model in which BRCA mutation status is associated with functional differences within broadly conserved spatial regions, rather than extensive reorganization of the overall spatial architecture. This spatially resolved framework identifies BRCA-associated immune transcriptional patterns in HGSOC and provides a basis for future mechanistic validation.