VHL (von Hippel-Lindau tumor suppressor)

Endoscopic ultrasound with fine-needle aspiration was performed and standard cyst fluid analysis was nondiagnostic, but cyst fluid NGS identified a pathogenic VHL mutation. This case highlights the utility of cyst fluid NGS in uncovering hereditary cancer syndromes when conventional analyses are inconclusive.

Identification of the VHL gene mutation required genetic counseling of all family members, during which a similar mutation was identified in the younger brother. Surgical treatment is the main method of treating FHL syndrome, but advances in genetic research technologies provide new opportunities for the treatment of tumors associated with this syndrome.

By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.

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

These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.

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

On the translational front, HIF-2α inhibitors (such as belzutifan), strategies that suppress or oxidize lipids to trigger ferroptosis, and interventions targeting glutamine and one-carbon metabolism show promise when rationally combined with ICIs, TKIs, or anti-angiogenic therapies. We propose a stratified decision framework anchored in DCCD state, lipid-droplet/PLIN2 phenotype, ferroptosis sensitivity, and HIF activity, and discuss the emerging roles of radiopathomics (e.g., CT HU-PLIN2 coupling) and circulating metabolic fingerprints in companion diagnostics. Looking toward clinical deployment, advancing standardization within MSI/IBSI and FAIR data principles-and launching biomarker-enriched, prospective multicenter trials-will be essential to demonstrate the real-world value of precision metabolic oncology in the personalized treatment of ccRCC.