Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Histopathology. 2019 Dec;75(6):865-875. doi: 10.1111/his.13958. Epub 2019 Oct 23.
Nested variant of urothelial carcinoma (NVUC) is rare, and only a few small series exist. Molecular characteristics and the classifying marker profile as well as therapeutic targets of this specific variant are mostly unknown. The aim of this study was to characterise NVUC at the molecular level in one of the largest cohorts to date. In addition, we applied an immunohistochemical marker panel in order to define the molecular subtype.
Sixty NVUC cases were collected from different departments. TERT promoter mutation analysis was carried out in all samples using SNaPshot analysis. Targeted sequencing of 48 cancer-related genes by next-generation sequencing (NGS) analysis was performed in a subset of 26 cases. Immunohistochemical markers CD44, CK5, CK14, EGFR, p63, FOXA1, GATA3, CD24 and CK20 were used to elucidate the molecular subtype. A total of 62.5% of NVUC cases harboured a mutation of the TERT promoter. Additionally, TP53, JAK3 and CTNNB1 were among the most frequently mutated genes identified by NGS analysis. Subtyping revealed that all NVUC express luminal markers such as CD24, FOXA1, GATA3 and CK20.
In summary, NVUC belong to the luminal molecular subtype. Moreover, a subset of NVUC seems to be characterised by mutations of the Wnt and inflammatory pathways, including JAK3 mutations, indicating a different biological background compared to conventional urothelial bladder cancer.
尿路上皮癌巢变体（NVUC）罕见，目前仅有少数小系列报道。这种特殊变体的分子特征、分类标志物特征以及治疗靶点大多未知。本研究旨在对迄今为止最大的队列之一进行 NVUC 的分子水平分析。此外，我们应用了免疫组织化学标志物面板来定义分子亚型。
从不同科室收集了 60 例 NVUC 病例。所有样本均采用 SNaPshot 分析进行 TERT 启动子突变分析。在 26 例病例的亚组中，通过下一代测序（NGS）分析进行了 48 个与癌症相关的基因的靶向测序。使用 CD44、CK5、CK14、EGFR、p63、FOXA1、GATA3、CD24 和 CK20 等免疫组织化学标志物来阐明分子亚型。共有 62.5%的 NVUC 病例存在 TERT 启动子突变。此外，TP53、JAK3 和 CTNNB1 是 NGS 分析确定的最常突变基因之一。亚型分析显示，所有 NVUC 均表达 luminal 标志物，如 CD24、FOXA1、GATA3 和 CK20。
总之，NVUC 属于 luminal 分子亚型。此外，亚组的 NVUC 似乎具有 Wnt 和炎症途径的突变，包括 JAK3 突变，表明与传统的膀胱癌相比具有不同的生物学背景。
