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Peer-reviewedCC BY 4.0PLOS Genetics

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

  • Jing Qian1
  • Rania Bassiouni2
  • Yuxin Jin2
  • Seeta Rajpara1
  • Monica Neuman3
  • Varun U. Khetan3
  • Bodour Salhia1
  • David W. Craig2
  • Joseph W. Carlson4
  • Lynda D. Roman5
  • John D. Carpten2
5 affiliations
  1. 1Department of Cancer Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
  2. 2Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America
  3. 3Department of Obstetrics and Gynecology, Los Angeles General Medical Center, Los Angeles, California, United States of America
  4. 4Department of Pathology, City of Hope, Duarte, California, United States of America
  5. 5Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
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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. Author summary: High-grade serous ovarian cancer is the most common and aggressive form of ovarian cancer. Many tumors carry changes in BRCA1 or BRCA2, genes involved in DNA repair, but it remains unclear how these genetic differences relate to tumor organization and immune activity. This study defines the spatial and molecular features of BRCA-MT and BRCA-WT high-grade serous ovarian cancer using integrated genomic, transcriptomic, and spatial transcriptomic analyses. We found that BRCA-MT and BRCA-WT tumors shared much of their overall tissue architecture. However, immune-related activity differed within specific spatial regions. In particular, BRCA-MT tumors showed stronger interferon and antigen-presentation programs within a recurrent immune-enriched region. Additional computational analyses supported enrichment of immune-cell signals in this region, while a macrophage-rich region appeared more broadly conserved across tumors. These findings suggest that BRCA status may influence the functional immune state of recurrent spatial regions in the tumor microenvironment. Our study provides a spatial framework for future work testing how tumor genetics shapes immune heterogeneity in ovarian cancer.

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Cite

BibTeXRIS
BibTeX
@article{qian2026multiomics,
  title = {{Multi-omics analysis of high-grade serous ovarian cancers reveals heterogeneity and distinct immunological patterns based upon clinico-genomic status}},
  author = {Jing Qian and Rania Bassiouni and Yuxin Jin and Seeta Rajpara and Monica Neuman and Varun U. Khetan and Bodour Salhia and David W. Craig and Joseph W. Carlson and Lynda D. Roman and John D. Carpten},
  journal = {PLOS Genetics},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pgen.1012355},
  url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012355},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Multi-omics analysis of high-grade serous ovarian cancers reveals heterogeneity and distinct immunological patterns based upon clinico-genomic status
AU  - Jing Qian
AU  - Rania Bassiouni
AU  - Yuxin Jin
AU  - Seeta Rajpara
AU  - Monica Neuman
AU  - Varun U. Khetan
AU  - Bodour Salhia
AU  - David W. Craig
AU  - Joseph W. Carlson
AU  - Lynda D. Roman
AU  - John D. Carpten
PY  - 2026
DA  - 2026/10/22
JO  - PLOS Genetics
DO  - 10.1371/journal.pgen.1012355
UR  - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012355
AB  - 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. Author summary: High-grade serous ovarian cancer is the most common and aggressive form of ovarian cancer. Many tumors carry changes in BRCA1 or BRCA2, genes involved in DNA repair, but it remains unclear how these genetic differences relate to tumor organization and immune activity. This study defines the spatial and molecular features of BRCA-MT and BRCA-WT high-grade serous ovarian cancer using integrated genomic, transcriptomic, and spatial transcriptomic analyses. We found that BRCA-MT and BRCA-WT tumors shared much of their overall tissue architecture. However, immune-related activity differed within specific spatial regions. In particular, BRCA-MT tumors showed stronger interferon and antigen-presentation programs within a recurrent immune-enriched region. Additional computational analyses supported enrichment of immune-cell signals in this region, while a macrophage-rich region appeared more broadly conserved across tumors. These findings suggest that BRCA status may influence the functional immune state of recurrent spatial regions in the tumor microenvironment. Our study provides a spatial framework for future work testing how tumor genetics shapes immune heterogeneity in ovarian cancer.
SN  - 1553-7404
SN  - 1553-7390
ER  -