{
  "abstract": "Clear cell renal cell carcinoma (ccRCC) is biologically heterogeneous, and epithelial-mesenchymal plasticity contributes to invasion and treatment resistance. We aimed to develop a distal-less homeobox 4 (DLX4)-anchored pathomics model for overall survival (OS) and to relate routine hematoxylin and eosin (H&E) morphology to malignant epithelial and spatial states. This retrospective secondary analysis used public The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) ccRCC data accessed and frozen in June 2026. Patients with ccRCC, positive OS time, known vital status, and matched whole-slide-image pathomics features were eligible. TCGA was used for model fitting (506 patients; 167 deaths). CPTAC (94 patients; 20 deaths) contributed to cross-cohort feature confirmation and algorithm ranking and therefore was not an untouched external-validation cohort. Epithelial-mesenchymal transition (EMT) genes were screened using database of epithelial-mesenchymal transition (dbEMT) and least absolute shrinkage and selection operator-Cox regression (LASSO-Cox). Direction-consistent DLX4-associated features were filtered in TCGA and evaluated in a 101-style survival machine-learning library. The final eight-component partial least squares Cox (plsRcox) model used 705 standardized predictors. Bulk, single-cell, copy-number, trajectory, and spatial analyses were used for biological interpretation. LASSO-Cox retained 19 EMT genes, and DLX4 was prioritized as an adverse-prognosis anchor. Of 1,192 direction-consistent DLX4-pathomics features, 705 passed TCGA univariable Cox filtering. Of 117 prespecified parameterized jobs, 63 generated finite paired TCGA-CPTAC risk scores and were evaluable. The selected plsRcox model yielded an apparent TCGA C-index of 0.877 [95% confidence interval (CI): 0.853-0.900] and a CPTAC cross-cohort C-index of 0.775 (95% CI: 0.617-0.915). The fixed TCGA median cutoff separated CPTAC low-risk (44 patients; 4 deaths) and high-risk (50 patients; 16 deaths) groups (log-rank P=0.008). Adding the pathomics score to age, stage, and grade increased the C-index in TCGA by 0.121 (95% CI: 0.089-0.158), but this increment was not reproduced in CPTAC (-0.019; 95% CI: -0.184 to 0.118). The DLX4-associated pathomics score was associated with OS and with malignant epithelial and spatial remodeling in ccRCC. Because CPTAC influenced feature confirmation and algorithm ranking, its performance is a cross-cohort evaluation rather than unbiased external validation. The model and its incremental clinical value require locked, independent multicenter evaluation before clinical use.",
  "abstract_shown": true,
  "affiliations": [
    "School of Clinical Medicine, Shandong Second Medical University, Weifang, China.",
    "Department of Urology, Qingdao Municipal Hospital, Qingdao, China.",
    "The 14th Retired Cadre Rest Institute of the Chinese People's Liberation Army in Dalian, Dalian, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Guangli Fang",
      "orcid": "0009-0009-8517-6761"
    },
    {
      "affs": [
        2
      ],
      "name": "Xinmiao Bao"
    },
    {
      "affs": [
        1
      ],
      "name": "Jingyu Chang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Fuzhou Sun"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhilei Qiu",
      "orcid": "0000-0002-3217-5337"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8040vsmjevtr7.bib",
  "cited_by": 0,
  "doi": "10.21037/tau-2026-0653",
  "fulltext_url": "https://europepmc.org/articles/PMC13741081",
  "id": "8040vsmjevtr7",
  "issns": [
    "2223-4691"
  ],
  "landing_url": "https://europepmc.org/article/MED/42997161",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Renal cell carcinoma treatment"
    ]
  ],
  "openalex": "W7223811128",
  "pdf_url": "https://europepmc.org/articles/PMC13741081?pdf=render",
  "pmcid": "PMC13741081",
  "pmid": "42997161",
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8040vsmjevtr7.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42997161",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42997161"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Renal cell carcinoma treatment",
      "subfield": "oncology"
    }
  ],
  "title": "Development and cross-cohort evaluation of a DLX4-associated epithelial-mesenchymal transition pathomics signature for overall survival in clear cell renal cell carcinoma.",
  "title_text": "Development and cross-cohort evaluation of a DLX4-associated epithelial-mesenchymal transition pathomics signature for overall survival in clear cell renal cell carcinoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/8040vsmjevtr7",
  "venue": "Translational andrology and urology",
  "versions": []
}