Background and objective

Molecular classification of upper tract urothelial carcinoma (UTUC) can provide insight into divergent clinical outcomes and provide a biological rationale for clinical decision-making. As such, we performed multi-omic analysis of UTUC tumors to identify molecular features associated with disease recurrence and response to immune checkpoint blockade (ICB).

Methods

Targeted DNA and whole transcriptome RNA sequencing was performed on 100 UTUC tumors collected from patients undergoing nephroureterectomy. Consensus non-negative matrix factorization was used to identify molecular clusters associated with clinical outcomes. Gene set enrichment and immune deconvolution analyses were performed. Weighted gene co-expression network analysis was employed for unsupervised identification of gene networks in each cluster.

Key findings and limitations

Five molecular clusters with distinct clinical outcomes were identified. Favorable subtypes (C1 and C2) were characterized by a luminal-like signature and an immunologically depleted tumor microenvironment (TME). Subtype C3 was characterized by FGFR3 alterations and a higher tumor mutational burden, and included all tumors with microsatellite instability. Despite higher rates of recurrence and inferior survival, subtypes C4 and C5 harbored an immunologically rich TME favoring response to ICB. Limitations include extrapolation of molecular features of tumors from the primary site to determine response to systemic immunotherapy and the limited resolution of bulk sequencing to distinguish gene expression in the tumor, stroma, and immune compartments.

Conclusions and clinical implications

RNA sequencing identified previously underappreciated UTUC molecular heterogeneity and suggests that UTUC patients at the highest risk of metastatic recurrence following surgery include those most likely to benefit from perioperative ICB.

中文翻译：

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分子异质性和免疫浸润驱动上尿路尿路上皮癌的临床结局

 背景和目标

上尿路尿路上皮癌 （UTUC） 的分子分类可以深入了解不同的临床结果，并为临床决策提供生物学依据。因此，我们对 UTUC 肿瘤进行了多组学分析，以确定与疾病复发和免疫检查点阻断 （ICB） 反应相关的分子特征。

 方法

对从肾输尿管切除术患者收集的 100 例 UTUC 肿瘤进行靶向 DNA 和全转录组 RNA 测序。采用共识非负矩阵分解来确定与临床结局相关的分子簇。进行基因集富集和免疫反卷积分析。采用加权基因共表达网络分析对每个簇中的基因网络进行无监督鉴定。

主要发现和局限性

确定了 5 个具有不同临床结局的分子簇。有利亚型 （C1 和 C2） 的特征是管腔样特征和免疫耗尽的肿瘤微环境 （TME）。亚型 C3 以 FGFR3 改变和较高的肿瘤突变负荷为特征，包括所有具有微卫星不稳定的肿瘤。尽管复发率较高且生存率较低，但亚型 C4 和 C5 携带免疫学丰富的 TME，有利于对 ICB 的反应。局限性包括从原发部位推断肿瘤的分子特征以确定对全身免疫治疗的反应，以及用于区分肿瘤、基质和免疫区室中基因表达的批量测序的分辨率有限。

结论和临床意义

RNA 测序确定了以前被低估的 UTUC 分子异质性，并表明手术后转移复发风险最高的 UTUC 患者包括最有可能从围手术期 ICB 中受益的患者。