Whole-Genome Landscape of Retinal Hemangioblastomas

Area of Science:

• Oncology
• Genetics
• Ophthalmology

Background:

• Retinal hemangioblastomas (RHs) are rare benign vascular tumors, often associated with Von Hippel-Lindau (VHL) syndrome.
• Limited molecular studies exist for RHs compared to other VHL-associated tumors.
• The precise molecular drivers of RH tumorigenesis remain unclear.

Purpose of the Study:

• To investigate the molecular basis of retinal hemangioblastomas (RHs) in the context of Von Hippel-Lindau (VHL) syndrome.
• To determine if VHL alterations alone are sufficient to drive RH tumorigenesis.
• To identify genetic alterations and gene expression changes in RHs.

Main Methods:

• Whole-genome sequencing (WGS) of germline and RH DNA from five patients.
• RNA sequencing of RH biopsies, unaffected retinas, and choroid controls.
• Comparative analysis of genomic and transcriptomic data.

Main Results:

• Germline variants and copy number losses in the VHL gene were identified.
• Mosaic loss of chromosome 3 was consistently found in RH biopsies, indicating the second hit.
• Few additional deleterious somatic variants were detected, suggesting limited somatic changes.
• Reduced VHL expression and downstream gene expression alterations were observed in RHs via RNA sequencing.

Conclusions:

• Retinal hemangioblastomas exhibit a limited number of somatic genetic changes.
• Loss of chromosome 3 is the probable second hit in RHs with germline VHL alterations.
• VHL variants significantly impact downstream gene expression, with domain-specific effects observed.