PO.CL12.01 · 临床研究
非肌层浸润性膀胱癌的分子异质性揭示了具有相反卡介苗（Bacillus Calmette-Guérin）反应和临床结局的临床分化亚型
Molecular heterogeneity in non-muscle invasive bladder cancer reveals clinically divergent subtypes with contrasting Bacillus Calmette-Guérin response and clinical outcomes
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摘要 Abstract
中文摘要
背景：非肌层浸润性膀胱癌（NMIBC）是一种早期、分子异质性的恶性肿瘤，其临床结局多样，从频繁复发到偶发进展不等。与肌层浸润性膀胱癌（MIBC）不同，NMIBC缺乏统一的分子亚型。当前的分类系统提供了生物学见解，但预后精确度有限。尽管复发和进展常被视为一个连续过程，但复发肿瘤通常表现出卡介苗（BCG）耐药，而进展性肿瘤往往对BCG有反应，这凸显了对精确分子分类的需求。
方法：通过整合十种既有的基于组学的NMIBC分类器，我们识别出六种临床和分子上截然不同的亚型。每种亚型选取50个代表性基因（共300个），命名为NMIBC分子异质性300基因特征（MHN300），用于构建基于AutoML的预测模型。该模型在11个独立的NMIBC队列和7个单细胞RNA测序数据集上进行了训练和验证。每种亚型均接受了全面的分子表征，包括转录组学和基因组学分析，并使用Kaplan-Meier和Cox回归分析评估其预后相关性。
结果：通过整合十种既有分类器，定义了六种分子和临床上截然不同的NMIBC亚型（C1-C6）。C1表现出早期细胞周期和尿空斑蛋白（uroplakin）活性，而C2显示出泛成纤维细胞TGF-beta和EMT信号。C3结合了强免疫和晚期细胞周期程序，而C4和C5均以晚期细胞周期激活为特征但临床行为相反；C4显示出良好的BCG反应和延长的无进展生存期（PFS，log-rank检验P < 0.001），而C5表现为高频复发的NMIBC（24%每年≥2次复发，HR = 5.12，95% CI 2.82-9.39，log-rank检验P < 0.001），并伴有BCG耐药和scRNA-seq中的内皮细胞富集。C6表现出FGFR3和早期细胞周期特征。MHN300 AutoML分类器达到0.88的准确率，并在独立队列中得到验证。
结论：MHN300分类器通过解析亚型内异质性并划分出生物学上连贯、临床上有意义、具有不同复发和进展风险的亚组，改进了当前NMIBC的分子框架。这一改进的分类学为NMIBC的亚型指导精准管理奠定了基础。
资助支持：本研究由韩国生命科学与生物技术研究院（KRIBB）研究计划项目（KGM5192423）资助。
查看英文原文 English abstract
Background: Non-muscle-invasive bladder cancer (NMIBC) is an early-stage, molecularly heterogeneous malignancy with diverse clinical outcomes from frequent recurrence to occasional progression. Unlike muscle-invasive bladder cancer (MIBC), NMIBC lacks a unified molecular subtype. Current classification systems provide biological insights but offer limited prognostic precision. Although recurrence and progression are often treated as a continuum, recurrent tumors commonly exhibit Bacillus Calmette-Guérin (BCG) resistance, whereas progressive tumors tend to respond to BCG, highlighting the need for a precise molecular classification.
Methods: By integrating ten previously established omics-based classifiers of NMIBC, we identified six clinically and molecularly distinct subtypes. Fifty representative genes per subtype (300 total), designated as the Molecular Heterogeneity of NMIBC 300-gene signature (MHN300), were selected to build an AutoML-based prediction model. The model was trained and validated across 11 independent NMIBC cohorts and 7 single-cell RNA-seq datasets. Each subtype underwent comprehensive molecular characterization, including transcriptomic and genomic analyses, and prognostic relevance was assessed using Kaplan-Meier and Cox regression analyses.
Results: Six molecularly and clinically distinct NMIBC subtypes (C1-C6) were defined through integration of ten prior classifiers. C1 exhibited early cell-cycle and uroplakin activity, whereas C2 showed pan-fibroblast TGF-beta and EMT signaling. C3 combined strong immune and late cell-cycle programs, while C4 and C5 both featured late cell-cycle activation with opposing clinical behaviors; C4 showing favorable BCG response and prolonged progression-free survival (PFS, P < 0.001 by log-rank test), and C5 displayed a high-frequency recurrence NMIBC (24% with ≥2 recurrence per year, HR = 5.12, 95% CI 2.82-9.39, P < 0.001 by log-rank test), along with BCG resistance and endothelial enrichment in scRNA-seq. C6 demonstrated FGFR3 and early cell-cycle features. The MHN300 AutoML classifier achieved 0.88 accuracy and was validated across independent cohorts.
Conclusions: The MHN300 classifier refines the current molecular framework for NMIBC by resolving intra-subtype heterogeneity and delineating biologically coherent, clinically meaningful subgroups with distinct risks of recurrence and progression. This refined taxonomy provides a foundation for subtype-guided precision management of NMIBC.
Grant Support: This study was supported by grants from the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM5192423).
利益披露 Disclosure
J. Seo, None..
I. Jeong, None..
Y. Yoon, None..
J. Kim, None..
S. Kim, None..
S. Baek, None..
S. Kim, None.