Exploring vertical genomic heterogeneity and chemotherapy response using targeted genomic sequencing in muscle-invasive bladder cancer
7 affiliations
- 1Division of Urology, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan
- 2Division of Artificial Intelligence and Digital Health Science, Department of Social/Community Medicine and Health Science, Kobe University Graduate School of Medicine, Kobe, Japan
- 3Division of Integrated Analyses of Bioresource and Healthcare, Department of Future Medical Sciences, Kobe University Graduate School of Medicine, Kobe, Japan
- 4Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
- 5Department of Integrated Analytics, M&D Data Science Center, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan
- 6Riken Genesis Co. LTD, Tokyo, Japan
- 7Central Research Laboratories, Sysmex Corporation, Kobe, Japan
Abstract
Background: We performed a targeted genomic sequence of muscle-invasive bladder cancer (MIBC) tissues to investigate vertical intratumoral heterogeneity, invasion processes, and potential biomarkers of platinum-based neoadjuvant chemotherapy (NAC) efficacy in MIBC.
Methods: Mutations in key genes thought to be associated with MIBC were investigated using deep amplicon sequencing of tissue samples from 34 Japanese patients with MIBC, including paired superficial and deep layers from seven patients. Genetic mutations linked to the NAC response were identified by stratifying patients into NAC responder and non-responder groups.
Results: Somatic mutations were detected in 91.2% of cases, with TP53 mutations being the most common (50%). Pathogenic mutations in superficial and deep layers were concordant only in 2 of the 7 cases, and the concordance disappeared when including non-pathogenic mutations. In one case, TP53 mutations were found only in deep layer. Immunohistochemical staining revealed differential expression of epithelial–mesenchymal transition-related molecules in the superficial and deep layers. ERCC excision repair 2 gene (ERCC2) mutations were identified more frequently in NAC responders compared with non-responders (50% vs. 0%), whereas the reverse was true for TP53 mutations (16.7% vs. 42.9%).
Conclusions: Our results suggest that ERCC2 and TP53 mutations are potential biomarkers of the response to NAC and that evaluating deep tumor layers may be considered to care about vertical heterogeneity.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12894-026-02265-4.
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BibTeX
@article{tobe2026exploring,
title = {{Exploring vertical genomic heterogeneity and chemotherapy response using targeted genomic sequencing in muscle-invasive bladder cancer}},
author = {Taisuke Tobe and Yoshiharu Miyata and Yoshinori Nakamura and Takuto Hara and Tomoaki Terakawa and Jun Teishima and Koji Chiba and Takayuki Kodama and Takanori Hasegawa and Naoto Kondo and Toshiyuki Sato and Hideaki Miyake and Raizo Yamaguchi and Hiroshi Matsuoka},
journal = {BMC Urology},
year = {2026},
month = aug,
doi = {10.1186/s12894-026-02265-4},
url = {https://doi.org/10.1186/s12894-026-02265-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Exploring vertical genomic heterogeneity and chemotherapy response using targeted genomic sequencing in muscle-invasive bladder cancer
AU - Taisuke Tobe
AU - Yoshiharu Miyata
AU - Yoshinori Nakamura
AU - Takuto Hara
AU - Tomoaki Terakawa
AU - Jun Teishima
AU - Koji Chiba
AU - Takayuki Kodama
AU - Takanori Hasegawa
AU - Naoto Kondo
AU - Toshiyuki Sato
AU - Hideaki Miyake
AU - Raizo Yamaguchi
AU - Hiroshi Matsuoka
PY - 2026
DA - 2026/08/07
JO - BMC Urology
DO - 10.1186/s12894-026-02265-4
UR - https://doi.org/10.1186/s12894-026-02265-4
AB - Background: We performed a targeted genomic sequence of muscle-invasive bladder cancer (MIBC) tissues to investigate vertical intratumoral heterogeneity, invasion processes, and potential biomarkers of platinum-based neoadjuvant chemotherapy (NAC) efficacy in MIBC. Methods: Mutations in key genes thought to be associated with MIBC were investigated using deep amplicon sequencing of tissue samples from 34 Japanese patients with MIBC, including paired superficial and deep layers from seven patients. Genetic mutations linked to the NAC response were identified by stratifying patients into NAC responder and non-responder groups. Results: Somatic mutations were detected in 91.2% of cases, with TP53 mutations being the most common (50%). Pathogenic mutations in superficial and deep layers were concordant only in 2 of the 7 cases, and the concordance disappeared when including non-pathogenic mutations. In one case, TP53 mutations were found only in deep layer. Immunohistochemical staining revealed differential expression of epithelial–mesenchymal transition-related molecules in the superficial and deep layers. ERCC excision repair 2 gene (ERCC2) mutations were identified more frequently in NAC responders compared with non-responders (50% vs. 0%), whereas the reverse was true for TP53 mutations (16.7% vs. 42.9%). Conclusions: Our results suggest that ERCC2 and TP53 mutations are potential biomarkers of the response to NAC and that evaluating deep tumor layers may be considered to care about vertical heterogeneity. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12894-026-02265-4.
SN - 1471-2490
ER -