Gustave Roussy, DITEP, Gustave Roussy, Villejuif, France.
INSERM 981, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
Nat Commun. 2024 Oct 4;15(1):8603. doi: 10.1038/s41467-024-52915-0.
Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases.
转移性尿路上皮癌（mUC）是一种致命的癌症，治疗选择有限。早期大规模研究提供了对非转移性 UC 的基因组和转录组特征的重要见解。然而，mUC 的基因组图谱仍不清楚。我们对 111 名转移性活检样本进行了全外显子（WES）和 mRNA 测序（RNA-seq），结果表明 mUC 的驱动基因突变与原发性 UC（TCGA 数据）相似。APOBEC、铂类和 HRD 突变特征在 mUC 中最为常见，分别在 56%、14%和 9%的 mUC 样本中被识别。在 mUC 中使用共识转录组分类进行的分子亚型分析显示，神经内分泌亚型富集。配对样本分析揭示了亚型异质性和时间演变。我们在 73%的 mUC 患者中确定了潜在的治疗靶点，其中 FGFR3（26%）、ERBB2（7%）、TSC1（7%）和 PIK3CA（13%）最为常见。NECTIN4 和 TACSTD2 的表达不受分子亚型、FGFR3 改变和转移部位的影响。
