{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cancer Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America",
    "Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, California, United States of America",
    "Department of Obstetrics and Gynecology, Los Angeles General Medical Center, Los Angeles, California, United States of America",
    "Department of Pathology, City of Hope, Duarte, California, United States of America",
    "Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jing Qian",
      "orcid": "0009-0008-7026-9386"
    },
    {
      "affs": [
        1
      ],
      "name": "Rania Bassiouni",
      "orcid": "0000-0002-4754-9311"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuxin Jin",
      "orcid": "0000-0002-6124-9681"
    },
    {
      "affs": [
        0
      ],
      "name": "Seeta Rajpara"
    },
    {
      "affs": [
        2
      ],
      "name": "Monica Neuman"
    },
    {
      "affs": [
        2
      ],
      "name": "Varun U. Khetan",
      "orcid": "0000-0003-2825-2157"
    },
    {
      "affs": [
        0
      ],
      "name": "Bodour Salhia"
    },
    {
      "affs": [
        1
      ],
      "name": "David W. Craig",
      "orcid": "0000-0003-2040-1955"
    },
    {
      "affs": [
        3
      ],
      "name": "Joseph W. Carlson",
      "orcid": "0000-0002-3006-4107"
    },
    {
      "affs": [
        4
      ],
      "name": "Lynda D. Roman"
    },
    {
      "affs": [
        1
      ],
      "name": "John D. Carpten",
      "orcid": "0000-0002-6862-2821"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cv166k6kpw83j.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012355",
  "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012355",
  "id": "cv166k6kpw83j",
  "issns": [
    "1553-7404",
    "1553-7390"
  ],
  "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012355",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Basic Cancer Research"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Biology and life sciences"
    ],
    [
      "heading",
      "Cancer Genomics"
    ],
    [
      "heading",
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    ],
    [
      "heading",
      "Cancers and Neoplasms"
    ],
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      "heading",
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    ],
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      "heading",
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    ],
    [
      "heading",
      "Genetic Causes of Cancer"
    ],
    [
      "heading",
      "Genetics"
    ],
    [
      "heading",
      "Genome Analysis"
    ],
    [
      "heading",
      "Genomic Medicine"
    ],
    [
      "heading",
      "Genomics"
    ],
    [
      "heading",
      "Gynecological Tumors"
    ],
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      "heading",
      "Malignant Tumors"
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      "Medical Risk Factors"
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      "heading",
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    [
      "heading",
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      "heading",
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    [
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      "heading",
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      "heading",
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      "Transcriptome Analysis"
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      "openalex",
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    ],
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      "/Biology and life sciences/Computational biology/Genome analysis/Transcriptome analysis"
    ],
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      "/Biology and life sciences/Genetics/Genomics/Genome analysis/Transcriptome analysis"
    ],
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      "/Biology and life sciences/Genetics/Genomics/Genomic medicine/Cancer genomics"
    ],
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      "plos",
      "/Biology and life sciences/Genetics/Mutation/Somatic mutation"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Sequencing techniques/RNA sequencing"
    ],
    [
      "plos",
      "/Medicine and health sciences/Epidemiology/Medical risk factors/Cancer risk factors/Genetic causes of cancer"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Basic cancer research/Cancer genomics"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancer risk factors/Genetic causes of cancer"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Gynecological tumors/Ovarian cancer"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Malignant tumors"
    ],
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      "plos",
      "/Research and analysis methods/Molecular biology techniques/Sequencing techniques/RNA sequencing"
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  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012355&type=printable",
  "pmcid": "PMC13712742",
  "pmid": "42911976",
  "published": "2026-10-22",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/cv166k6kpw83j.ris",
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      "native_id": "10.1371/journal.pgen.1012355",
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "heading:Molecular biology",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "heading:Computational Biology",
      "subfield": "bioinformatics"
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    {
      "field": "biology",
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      "field": "medicine",
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      "field": "medicine",
      "origin": "plos:oncology",
      "subfield": "oncology"
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  "title": "Multi-omics analysis of high-grade serous ovarian cancers reveals heterogeneity and distinct immunological patterns based upon clinico-genomic status",
  "title_text": "Multi-omics analysis of high-grade serous ovarian cancers reveals heterogeneity and distinct immunological patterns based upon clinico-genomic status",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:15Z",
  "url": "https://research.draconitic.com/paper/cv166k6kpw83j",
  "venue": "PLOS Genetics",
  "versions": []
}