Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore.
Department of Urology, Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Suresnes, France; INSERM Unit 1015, Laboratoire de Recherche Translationnelle en Immunologie (LRTI), Gustave Roussy, Université Paris-Saclay, Villejuif, France.
Eur Urol. 2019 Mar;75(3):423-432. doi: 10.1016/j.eururo.2018.08.027. Epub 2018 Sep 10.
Previous molecular subtyping for bladder carcinoma (BLCA) involved <450 samples, with diverse classifications.
To identify molecular subtypes by curating a large BLCA dataset.
DESIGN, SETTING, AND PARTICIPANTS: Gene expression publicly available were combined and reanalyzed. The dataset contained 2411 unique tumors encompassing non-muscle-invasive (NMIBC) and muscle-invasive BLCA (MIBC). Subtypes were reproduced on The Cancer Genome Atlas, UROMOL, and IMvigor210.
Subtypes were assigned by gene expression.
Kaplan-Meier analyses were performed for subtype-clinical outcome correlations; Chi-square/Fisher exact tests were used for subtype-clinicopathological parameters associations.
We identified six molecular subtypes with different overall survival (OS) and molecular features. Subtype Neural-like (median OS, 87 mo) is prevalent in MIBC and characterized by high WNT/β-catenin signaling. HER2-like (107.7 mo) is distributed evenly across NMIBC and MIBC, with higher ERBB2 amplification and signaling. Papillary-like (>135 mo), an NMIBC subtype enriched in urothelial differentiation genes, shows a high frequency of actionable FGFR3 mutations, amplifications, and FGFR3-TACC3 fusion. Luminal-like (91.7 mo), predominantly NMIBC, has higher MAPK signaling and more KRAS and KMT2C/D mutations than other subtypes. Mesenchymal-like (MES; 86.6 mo) and Squamous-cell carcinoma-like (SCC; 20.6 mo) are predominant in MIBC. MES is high in AXL signaling, whereas SCC has elevated PD1, CTLA4 signaling, and macrophage M2 infiltration. About 20% of NMIBCs show MIBC subtype traits and a lower 5-yr OS rate than Papillary-like NMIBC (81% vs 96%). The main limitations of our study are the incomplete clinical annotation, and the analyses were based on transcriptome subset due to comparisons across gene expression quantification technologies.
BLCA can be stratified into six molecular subtypes. NMIBC, with a high risk of progression, displays the molecular features of MIBC.
Biomarkers are urgently needed to guide patient treatment selection and avoid unnecessary toxicities in those who fail to respond. We believe molecular subtyping is a promising way to tailor disease management for those who will benefit most.
先前的膀胱癌（BLCA）分子分型涉及 <450 个样本，分类多样。
通过整理大量 BLCA 数据集来确定分子亚型。
设计、设置和参与者：公开的基因表达数据被合并并重新分析。该数据集包含 2411 个独特的肿瘤，包括非肌肉浸润性（NMIBC）和肌肉浸润性 BLCA（MIBC）。在 The Cancer Genome Atlas、UROMOL 和 IMvigor210 上重现了这些亚型。
通过基因表达分配亚型。
我们确定了六个具有不同总体生存（OS）和分子特征的分子亚型。神经样亚型（中位 OS，87 个月）在 MIBC 中较为普遍，其特征是高水平的 WNT/β-catenin 信号。HER2 样亚型（107.7 个月）在 NMIBC 和 MIBC 中分布均匀，ERBB2 扩增和信号较高。乳头状样（>135 个月），一种富含尿路上皮分化基因的 NMIBC 亚型，FGFR3 突变、扩增和 FGFR3-TACC3 融合的频率较高。腔型（91.7 个月），主要为 NMIBC，MAPK 信号较高，KRAS 和 KMT2C/D 突变较其他亚型多。间充质样（MES；86.6 个月）和鳞状细胞癌样（SCC；20.6 个月）在 MIBC 中占主导地位。MES 中 AXL 信号较高，而 SCC 中 PD1、CTLA4 信号较高，巨噬细胞 M2 浸润较多。约 20%的 NMIBC 具有 MIBC 亚型特征，5 年 OS 率低于乳头状 NMIBC（81%比 96%）。本研究的主要局限性是临床注释不完整，并且由于比较了不同的基因表达定量技术，分析基于转录组子集。
BLCA 可分为六个分子亚型。有进展高风险的 NMIBC 表现出 MIBC 的分子特征。
迫切需要生物标志物来指导患者的治疗选择，并避免那些对治疗无反应的患者出现不必要的毒性。我们相信分子分型是为那些最受益的患者量身定制疾病管理的一种很有前途的方法。
