VHL mutation

Approximately 40% of PPGL harbor germline mutations, whereas somatic alterations account for additional subsets. Mutations in SDHx, VHL, RET, NF1, and other susceptibility genes define molecular clusters with distinct signaling pathways and clinical behavior, underscoring the importance of multidisciplinary, lifelong management.

P=N/A, N=1, Not yet recruiting, Fuzhou University Affiliated Provincial Hospital; Fuzhou University Affiliated Provincial Hospital

This study establishes the first H&E-based Pathomics framework for quantifying CAFs infiltration in RCC, providing a cost-effective and non-invasive tool for preliminary risk stratification. The model's strong correlation with collagen features and its ability to reveal underlying molecular mechanisms highlight its potential for potential value in understanding the stromal microenvironment, though further external validation is required for clinical translation.

P3, N=60, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Dec 2026

Importantly, CEBPB expression and enhancer activation were not modulated by VHL status and it could be targeted pharmacologically. The CEBPB-GPD1L-ether lipid-Akt-CPT1A axis is proposed as a new druggable driver in ccRCC integrating epigenetics, transcription, intermediary metabolism and oncogenic signaling.

Its favorable prognosis underscores the importance of distinguishing it from ccRCC to prevent unnecessary treatments. Further research is warranted to elucidate the underlying genetic mechanisms.

P2, N=130, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2027 --> Jan 2033 | Trial primary completion date: Jan 2026 --> Jan 2030

Variants affecting VHL impact downstream gene expression, variants impacting different VHL domains result in differential gene expression of these downstream targets. RNA sequencing may aid in the evaluation of variants of unknown significance.

We observed distinct molecular profiles between cysts and tumors, suggesting independent origins. While preliminary, these findings challenge the assumption that cysts always serve as precursors of ccRCC in VHL disease and underscore the need for larger studies to improve surveillance and management of renal lesions in patients with VHL disease.

Definitive diagnosis relies on pathology and immunohistochemistry. Surgical resection remains the primary treatment, and the prognosis is generally favorable.

Although guidelines recommend genetic counseling for all BRM patients, our findings suggest that testing was underutilized and diagnostic yield was low, particularly for high-risk mutations (e.g. VHL or FH-deficient RCC). These findings suggest that genetic testing for BRM patients could be considered selectively, prioritizing patients with extrarenal manifestations, family history, young age, or pathology suspicious for hereditary etiology.

P=N/A, N=150, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027