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

Area of Science:

• Genetics and Molecular Biology
• Oncology
• Nephrology

Background:

• Birt-Hogg-Dubé syndrome (BHD) is associated with kidney tumors, but their classification and the role of folliculin gene (FLCN) mutations are unclear.
• Existing diagnostic criteria for BHD-associated kidney tumors, including
• hybrid tumors,
• are ambiguous, necessitating a clearer understanding of FLCN alterations and tumor biology.

Purpose of the Study:

• To investigate the spectrum of FLCN alterations in BHD patients.
• To characterize the clinical outcomes of BHD patients with kidney tumors.
• To elucidate the molecular biology of FLCN-mutated tumors (FMTs) for improved diagnostic algorithms.

Main Methods:

• Germline FLCN alteration testing and outcome analysis in 20 BHD patients with 84 kidney tumors.
• Histopathological profiling of renal tumors.
• Next-generation sequencing, bulk/single-cell transcriptomic analysis, and immunohistochemistry (IHC).

Main Results:

• Identified 90 unique germline FLCN variants, including promoter deletions, in 234 families; 90% met NCCN germline testing criteria.
• Characterized 81 indolent FMTs, with only two nonconventional renal cell carcinoma patients showing metastases.
• FMTs exhibited a distinct gene expression profile from oncocytoma and Ch-RCC, with specific cell populations overexpressing GPNMB. IHC panels (L1CAM, SOX9, GPNMB) showed promise for screening conventional FMTs.

Conclusions:

• Current BHD germline testing strategies have gaps and should incorporate promoter deletion events.
• Multimodal molecular profiling translates to clinical practice via IHC biomarkers for improved BHD diagnosis.
• Distinguishing indolent conventional FMTs from potentially aggressive nonconventional tumors is crucial for patient management.