A 5-gene mutation signature predicts response to atezolizumab in metastatic bladder urothelial carcinoma.
- 1Center for Precision Cancer Medicine and Translation Research, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.
- 2Technology Transfer Department, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.
- 3Center for Precision Oncology Testing and Translational Research, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Abstract
Immune checkpoint inhibitors (ICIs) have improved outcomes in metastatic urothelial carcinoma, but predictive biomarkers beyond programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) are urgently needed. In this study, we aimed to identify a novel mutation-based signature that can accurately predict response to atezolizumab and to evaluate its predictive performance independently and in combination with TMB. We analyzed 298 patients from the IMvigor210 trial treated with atezolizumab. A 5-gene mutation signature comprising HOOK1, LGSN, PRR32, ADCY5, and ADAMTSL2 was derived via Fisher's exact test and least absolute shrinkage and selection operator (LASSO) regression. Patients were classified as mutation carriers (≥1 mutation in five genes) or non-carriers. We evaluated association with response, overall survival (OS), and pathway alterations. Among 298 response-evaluable patients, 214 with available mutation data were analyzed; 32 patients were mutation carriers. In the cohort, 32 patients were identified as mutation carriers. Mutation carriers had higher response rates than non-carriers (81.2% vs. 14.8%, P<0.001). The 5-gene mutation signature independently predicted response, while TMB did not (P=0.07). A combined TMB and 5-gene mutation signature model achieved AUC of 0.833, outperforming TMB (0.743) or signature (0.729) alone. Carriers had significantly prolonged OS [median not reached vs. 9.49 months; hazard ratio (HR) =0.105, P<0.001]. Gene Set Enrichment Analysis (GSEA) revealed cell cycle upregulation and downregulation of epithelial-mesenchymal transition (EMT)/angiogenesis/KRAS pathways in carriers. The 5-gene mutation signature is a robust independent predictor of response and survival in anti-PD-L1-treated metastatic urothelial cancer. Combining it with TMB enhances predictive accuracy, offering a practical strategy for patient selection in clinical practice.
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BibTeX
@article{han20265gene,
title = {{A 5-gene mutation signature predicts response to atezolizumab in metastatic bladder urothelial carcinoma.}},
author = {Dongmei Han and Caihong Wu and Dan Wang and Hao Jin and Weishuai Liu},
journal = {Translational andrology and urology},
year = {2026},
month = sep,
doi = {10.21037/tau-2026-0596},
url = {https://europepmc.org/article/MED/42997198},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A 5-gene mutation signature predicts response to atezolizumab in metastatic bladder urothelial carcinoma.
AU - Dongmei Han
AU - Caihong Wu
AU - Dan Wang
AU - Hao Jin
AU - Weishuai Liu
PY - 2026
DA - 2026/09/28
JO - Translational andrology and urology
DO - 10.21037/tau-2026-0596
UR - https://europepmc.org/article/MED/42997198
AB - Immune checkpoint inhibitors (ICIs) have improved outcomes in metastatic urothelial carcinoma, but predictive biomarkers beyond programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) are urgently needed. In this study, we aimed to identify a novel mutation-based signature that can accurately predict response to atezolizumab and to evaluate its predictive performance independently and in combination with TMB. We analyzed 298 patients from the IMvigor210 trial treated with atezolizumab. A 5-gene mutation signature comprising HOOK1, LGSN, PRR32, ADCY5, and ADAMTSL2 was derived via Fisher's exact test and least absolute shrinkage and selection operator (LASSO) regression. Patients were classified as mutation carriers (≥1 mutation in five genes) or non-carriers. We evaluated association with response, overall survival (OS), and pathway alterations. Among 298 response-evaluable patients, 214 with available mutation data were analyzed; 32 patients were mutation carriers. In the cohort, 32 patients were identified as mutation carriers. Mutation carriers had higher response rates than non-carriers (81.2% vs. 14.8%, P<0.001). The 5-gene mutation signature independently predicted response, while TMB did not (P=0.07). A combined TMB and 5-gene mutation signature model achieved AUC of 0.833, outperforming TMB (0.743) or signature (0.729) alone. Carriers had significantly prolonged OS [median not reached vs. 9.49 months; hazard ratio (HR) =0.105, P<0.001]. Gene Set Enrichment Analysis (GSEA) revealed cell cycle upregulation and downregulation of epithelial-mesenchymal transition (EMT)/angiogenesis/KRAS pathways in carriers. The 5-gene mutation signature is a robust independent predictor of response and survival in anti-PD-L1-treated metastatic urothelial cancer. Combining it with TMB enhances predictive accuracy, offering a practical strategy for patient selection in clinical practice.
SN - 2223-4691
ER -