{
  "abstract": "Background\n\nVariants of uncertain significance (VUS) in BRCA1/2 and other homologous recombination repair (HRR) genes represent a major interpretative challenge in prostate cancer, particularly in the next-generation sequencing era. While pathogenic alterations are associated with poor prognosis and therapeutic implications, the clinical impact of VUS remains unclear.Methods\n\nWe conducted a retrospective, real-world multicenter study including 1402 patients with metastatic castration-resistant prostate cancer (mCRPC) from 11 Italian academic centers (702 in the primary cohort; 700 in the validation cohort). Patients were stratified as wild-type (WT), pathogenic/likely pathogenic mutated (MUT), or VUS carriers in BRCA1/2 and other HRR genes. Overall survival (OS) was assessed using Kaplan-Meier estimates and Cox regression models. VUS were reclassified according to updated ENIGMA guidelines.Results\n\nIn the primary cohort, BRCA MUT and VUS were detected in 4.7 and 1.8% of patients, respectively, while other HRR MUT and VUS were observed in 14.1 and 14.0%. After re-evaluation, 7.7% of VUS changed classification, including three reclassified as clinically significant. For clinical outcome analyses, we restricted evaluation to patients harboring VUS located within functional domains. In the BRCA cohort, median OS from tumor diagnosis was significantly shorter in MUT (72 months) and VUS (74 months) compared with WT (144 months; p = 0.002). Similarly, in the HRR cohort, both MUT (104 months) and VUS (128 months) showed inferior OS compared to WT (144 months; p = 0.012). The secondary cohort confirmed a consistent prognostic gradient, with VUS demonstrating intermediate outcomes between WT and MUT groups (p < 0.001). No significant association was observed between VUS and response to first-line therapy in mCRPC. In multivariable analysis, BRCA1/2 pathogenic alterations retained a trend toward worse OS compared with WT patients (HR 1.78, 95% CI 0.96-3.30; p = 0.067), whereas BRCA1/2 VUS were not independently associated with OS after adjustment for major clinicopathological factors.Conclusions\n\nIn this large real-world study, VUS in BRCA/HRR genes were associated with intermediate but clinically relevant prognostic outcomes, suggesting potential biological significance. Although current guidelines do not support treatment decisions based on VUS, systematic re-evaluation and integration of functional data may refine risk stratification and improve precision oncology strategies in prostate cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Unit of Medical Oncology and Biomolecular Therapy and CREATE Center for Research and Innovation Medicine, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy.",
    "Molecular Pathology and Oncological Genetics Unit, Policlinico Riuniti, Foggia, Italy.",
    "Sovrintendenza Sanitaria Centrale, INAIL, Roma, Italy.",
    "Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy.",
    "Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.",
    "UOC di Oncologia, Azienda Ospedaliera di Rilievo Nazionale Cardarelli di Napoli, Naples, Italy.",
    "Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy.",
    "Department of Medical Oncology, Università degli Studi di Napoli Federico II, Naples, Italy.",
    "Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy.",
    "Oncology Unit, Oncology Department, \"Azienda Ospedaliero Universitaria (AOU) Dulbecco\" Hospital, Catanzaro, Italy.",
    "University Oncology Unit, University of Salento Fazzi Hospital, Lecce, Italy.",
    "Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.",
    "Medical Oncology, Ospedale Ca' Foncello di Treviso, AULSS2 Marca Trevigiana, Treviso, Italy.",
    "Unit of Medical Oncology, \"Sacro Cuore di Gesù\" Hospital, Gallipoli, Italy.",
    "Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.",
    "Newcastle Hospitals and NHS Trust, Newcastle upon Tyne, UK.",
    "Pathology Unit, Department of Clinical and Experimental Medicine, University of Foggia, Policlinico Riuniti, Foggia, Italy.",
    "IRCCS National Cancer Institute Regina Elena, Rome, Italy.",
    "Unit of Medical Oncology and Biomolecular Therapy and CREATE Center for Research and Innovation Medicine, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy. matteo.landriscina@unifg.it.",
    "Unit of Medical Oncology and Biomolecular Therapy and CREATE Center for Research and Innovation Medicine, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy. vincenza.conteduca@unifg.it."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
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        0
      ],
      "name": "Marianna Garofoli"
    },
    {
      "affs": [
        1
      ],
      "name": "Maria Iole Natalicchio"
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        0
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      "name": "Giuseppina Bruno"
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        2
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      "name": "Aldo Rosano"
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        3
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      "name": "Brigida Anna Maiorano"
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        4
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      "name": "Sabrina Rossetti"
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    {
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        5
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      "name": "Sarah Scagliarini"
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        6
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      "name": "Lorena Incorvaia"
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        7
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      "name": "Luigi Formisano"
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    {
      "affs": [
        8
      ],
      "name": "Ilaria Toma"
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    {
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        0
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      "name": "Guido Giordano"
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        7
      ],
      "name": "Giovanna Pecoraro"
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        9
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      "name": "Francesco Grillone"
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        0
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      "name": "Laura Palumbo"
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        10
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      "name": "Marco Pisino"
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    {
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        0
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      "name": "Marta Palladino"
    },
    {
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        0
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      "name": "Concetta Rita Di Pippo"
    },
    {
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        1
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      "name": "Valeria Bafunno"
    },
    {
      "affs": [
        11
      ],
      "name": "Nicole Brighi"
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    {
      "affs": [
        11
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      "name": "Chiara Casadei"
    },
    {
      "affs": [
        11
      ],
      "name": "Cristian Lolli"
    },
    {
      "affs": [
        12
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      "name": "Maria Concetta Cursano"
    },
    {
      "affs": [
        13
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      "name": "Vincenzo Emanuele Chiuri"
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    {
      "affs": [
        14,
        15
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      "name": "Pasquale Rescigno"
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    {
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        8
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      "name": "Emiliano Tamburini"
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    {
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      "name": "Francesca Sanguedolce"
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    {
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      "name": "Fabio Calabrò"
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    {
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        10
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      "name": "Ugo De Giorgi"
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    {
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        18
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      "name": "Matteo Landriscina"
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    {
      "affs": [
        19
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      "name": "Vincenza Conteduca"
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  "bibtex": "https://research.draconitic.com/paper/84hc753cjf5rc.bib",
  "cited_by": 0,
  "doi": "10.1186/s12916-026-05086-2",
  "fulltext_url": "https://europepmc.org/articles/PMC13726116",
  "id": "84hc753cjf5rc",
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  "language": "eng",
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      "1311|BRCA gene mutations in cancer"
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  "pdf_url": "https://europepmc.org/articles/PMC13726116?pdf=render",
  "pmcid": "PMC13726116",
  "pmid": "42972372",
  "published": "2026-08-04",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/84hc753cjf5rc.ris",
  "sources": [
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|BRCA gene mutations in cancer",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Prognostic impact of variants of uncertain significance (VUS) in BRCA genes and homologous recombination repair (HRR) genes in prostate cancer: a real-world multicenter study.",
  "title_text": "Prognostic impact of variants of uncertain significance (VUS) in BRCA genes and homologous recombination repair (HRR) genes in prostate cancer: a real-world multicenter study.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:22:09Z",
  "url": "https://research.draconitic.com/paper/84hc753cjf5rc",
  "venue": "BMC medicine",
  "versions": []
}