Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep;88(3):263-273.
doi: 10.1016/j.eururo.2025.03.012. Epub 2025 Apr 18.

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

Sounak Gupta  1 , Surendra Dasari  2 , Rachel R Warren  3 , Wei Shen  4 , Rhianna M Urban  4 , Melissa L Stanton  5 , Christine M Lohse  2 , Megan A Holdren  4 , Megan F Hoenig  4 , Beth A Pitel  4 , Stephanie A Smoley  4 , Stefan W Nelson  2 , Nate R Torell  4 , Autumn C Moon  4 , Leah M Nelson  4 , Joaquin J Garcia  4 , Peter C Lucas  4 , Kevin C Halling  4 , Benjamin R Kipp  4 , Stephen A Boorjian  6 , Stijn P De Langhe  3 , Lori A Erickson  4 , Vidit Sharma  6 , John C Cheville  4 , Bradley C Leibovich  6
Affiliations

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

Sounak Gupta et al. Eur Urol. 2025 Sep.

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.

Keywords: Birt-Hogg-Dubé syndrome; FOXI1; Folliculin gene; GPNMB; Hybrid tumors; L1CAM; SOX9; Single-cell RNA sequencing; Whole transcriptome analysis.

PubMed Disclaimer

MeSH terms

Supplementary concepts