Department of Pathology, Institut Curie, Saint-Cloud, France; Institut Curie, CNRS, UMR144, Equipe labellisée Ligue Contre le Cancer, Paris Sciences et Lettres Research University, Paris, France; Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Department of Urology, Bichat-Claude Bernard Hospital, Paris, France; Université de Paris, INSERM U976, Human Immunology, Pathophysiology, Immunotherapy, Paris, France.
Mod Pathol. 2023 Nov;36(11):100300. doi: 10.1016/j.modpat.2023.100300. Epub 2023 Aug 7.
Analyses of large transcriptomics data sets of muscle-invasive bladder cancer (MIBC) have led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUCs) are less known. Our objective was to determine the relevance of the consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors. Using immunohistochemistry (IHC), subtype markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16, Ki67, mismatch repair system proteins, and PD-L1 were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3'RNA sequencing of each tumor, with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression. Most of the 66 patients were men (77.3%), with pT1 (n = 23, 34.8%) or pT2-4 stage UTUC (n = 43, 65.2%). FGFR3 mutations and mismatch repair-deficient status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as luminal papillary (LumP). Combining our consensus classification results with those of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUCs, which was significantly higher than MIBCs. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology, and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular, if FGFR3 mutated. Our study shows that MIBC consensus classification robustly classified UTUCs and highlighted intratumoral molecular heterogeneity. The proportion of LumP was significantly higher in UTUCs than in MIBCs. Most LumP tumors showed low immune infiltration and PD-L1 expression and high proportion of FGFR3 mutations. These findings suggest differential response to novel therapies between patients with UTUC and those with MIBC.
对肌层浸润性膀胱癌（MIBC）的大型转录组学数据集的分析导致了共识分类。上尿路尿路上皮癌（UTUC）的分子亚型知之甚少。我们的目的是通过对新的手术治疗的≥pT1 肿瘤进行特征分析，确定共识分类在 UTUC 中的相关性。使用免疫组化（IHC），多重 GATA3-CK5/6-TUBB2B 标记物、CK20、p16、Ki67、错配修复系统蛋白和 PD-L1 进行评估。通过焦磷酸测序鉴定 FGFR3 突变。对每个肿瘤进行 3'RNA 测序，并在异质性病例中进行多采样。使用基因表达确定共识类、无监督组和微环境细胞丰度。大多数 66 名患者为男性（77.3%），其中 pT1（n=23，34.8%）或 pT2-4 期 UTUC（n=43，65.2%）。分别在 40%和 4.7%的病例中发现 FGFR3 突变和错配修复缺陷状态。共识亚型稳健地对 UTUC 进行分类，并反映了内在亚群。所有 pT1 肿瘤均被归类为 luminalpapillary（LumP）。将我们的共识分类结果与之前发表的 UTUC 队列结果相结合，LumP 肿瘤占≥pT2 UTUC 的 57.2%，明显高于 MIBC。10 名患者（15.2%）存在明显亚型的区域。共识类与 FGFR3 突变、分期、形态和 IHC 相关。大多数 LumP 肿瘤的特征是免疫浸润和 PD-L1 表达低，特别是如果 FGFR3 突变。我们的研究表明，MIBC 共识分类稳健地对 UTUC 进行分类，并强调了肿瘤内的分子异质性。LumP 在 UTUC 中的比例明显高于 MIBC。大多数 LumP 肿瘤显示低免疫浸润和 PD-L1 表达，以及 FGFR3 突变的高比例。这些发现表明，UTUC 患者与 MIBC 患者对新型治疗的反应可能不同。
