Birt-Hogg-Dubé综合征中的肾肿瘤：组织病理学、整体及单细胞转录组学综合分析

Renal Neoplasia in Birt-Hogg-Dubé Syndrome: Integrated Histopathologic, Bulk, and Single-cell Transcriptomic Analysis.

作者信息

Gupta Sounak, Dasari Surendra, Warren Rachel R, Shen Wei, Urban Rhianna M, Stanton Melissa L, Lohse Christine M, Holdren Megan A, Hoenig Megan F, Pitel Beth A, Smoley Stephanie A, Nelson Stefan W, Torell Nate R, Moon Autumn C, Nelson Leah M, Garcia Joaquin J, Lucas Peter C, Halling Kevin C, Kipp Benjamin R, Boorjian Stephen A, De Langhe Stijn P, Erickson Lori A, Sharma Vidit, Cheville John C, Leibovich Bradley C

机构信息

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

出版信息

Eur Urol. 2025 Sep;88(3):263-273. doi: 10.1016/j.eururo.2025.03.012. Epub 2025 Apr 18.

DOI:10.1016/j.eururo.2025.03.012

PMID:40253282

Abstract

BACKGROUND AND OBJECTIVE

It is unclear whether historically diagnosed "hybrid tumors" in patients with Birt-Hogg-Dubé syndrome (BHD) represent unique tumors or a hybrid between oncocytoma and chromophobe renal cell carcinoma (Ch-RCC), and existing diagnostic criteria are ambiguous. We aimed to understand the spectrum of folliculin gene (FLCN) alterations, outcomes for BHD patients with kidney tumors, and the biology of FLCN-mutated tumors (FMTs) to refine diagnostic algorithms.

METHODS

Germline testing for FLCN alterations and outcomes for 20 BHD patients with 84 kidney tumors were evaluated. Renal tumors were profiled for histopathology and analyzed using a combination of next-generation sequencing, bulk/single-cell transcriptomic analysis, and immunohistochemistry (IHC).

KEY FINDINGS AND LIMITATIONS

Ninety unique germline FLCN variants in 234 unrelated families included rare deletion events (14/234, 6%), including those of the promoter region. Most patients (17/19, 90%) met the National Comprehensive Cancer Network criteria for germline testing. Almost all cases represented indolent FMTs (n = 81), with metastases seen in two (of three) nonconventional renal cell carcinoma patients. FMTs showed a gene expression profile distinct from both oncocytoma and Ch-RCC characterized by four distinct L1CAM/FOXI1 and two L1CAM/FOXI1 cell populations that showed GPNMB overexpression. IHC panels that include L1CAM, SOX9, and GPNMB can be a reliable screen for conventional FMTs. Limitations include the absence of external transcriptomic datasets to avoid batch effects.

CONCLUSIONS AND CLINICAL IMPLICATIONS

Our results highlight the gaps in current clinical germline testing strategies for BHD, which should include promoter deletion events. Multimodal molecular profiling results can be translated into routine clinical practice using IHC biomarkers to improve the diagnosis of BHD and to separate indolent "conventional" FMTs from "nonconventional tumors," which may be clinically aggressive.

摘要

背景与目的

目前尚不清楚Birt-Hogg-Dubé综合征（BHD）患者中历史上诊断的“混合性肿瘤”是独特的肿瘤，还是嗜酸细胞瘤与嫌色肾细胞癌（Ch-RCC）之间的混合体，并且现有的诊断标准尚不明确。我们旨在了解卵泡抑素基因（FLCN）改变的范围、BHD肾肿瘤患者的预后以及FLCN突变肿瘤（FMTs）的生物学特性，以完善诊断算法。

方法

评估了20例患有84个肾肿瘤的BHD患者的FLCN改变的种系检测及预后情况。对肾肿瘤进行组织病理学分析，并结合二代测序、批量/单细胞转录组分析和免疫组织化学（IHC）进行分析。

主要发现与局限性

234个无关家族中的90个独特的种系FLCN变异包括罕见的缺失事件（14/234，6%），包括启动子区域的缺失。大多数患者（17/19，90%）符合美国国立综合癌症网络种系检测标准。几乎所有病例均为惰性FMTs（n = 81），三例非典型肾细胞癌患者中有两例出现转移。FMTs显示出与嗜酸细胞瘤和Ch-RCC均不同的基因表达谱，其特征为四个不同的L1CAM/FOXI1和两个L1CAM/FOXI1细胞群，这些细胞群显示GPNMB过表达。包括L1CAM、SOX9和GPNMB的IHC检测板可作为常规FMTs的可靠筛查方法。局限性包括缺乏外部转录组数据集以避免批次效应。