Development and cross-cohort evaluation of a DLX4-associated epithelial-mesenchymal transition pathomics signature for overall survival in clear cell renal cell carcinoma.
- 1School of Clinical Medicine, Shandong Second Medical University, Weifang, China.
- 2Department of Urology, Qingdao Municipal Hospital, Qingdao, China.
- 3The 14th Retired Cadre Rest Institute of the Chinese People's Liberation Army in Dalian, Dalian, China.
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.
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BibTeX
@article{fang2026development,
title = {{Development and cross-cohort evaluation of a DLX4-associated epithelial-mesenchymal transition pathomics signature for overall survival in clear cell renal cell carcinoma.}},
author = {Guangli Fang and Xinmiao Bao and Jingyu Chang and Fuzhou Sun and Zhilei Qiu},
journal = {Translational andrology and urology},
year = {2026},
month = sep,
doi = {10.21037/tau-2026-0653},
url = {https://europepmc.org/article/MED/42997161},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Development and cross-cohort evaluation of a DLX4-associated epithelial-mesenchymal transition pathomics signature for overall survival in clear cell renal cell carcinoma.
AU - Guangli Fang
AU - Xinmiao Bao
AU - Jingyu Chang
AU - Fuzhou Sun
AU - Zhilei Qiu
PY - 2026
DA - 2026/09/28
JO - Translational andrology and urology
DO - 10.21037/tau-2026-0653
UR - https://europepmc.org/article/MED/42997161
AB - 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.
SN - 2223-4691
ER -