Whole-Genome Landscape of Retinal Hemangioblastomas

Retinal hemangioblastomas (RHs) are rare benign vascular tumors that present mostly as manifestations of Von Hippel-Lindau (VHL) syndrome. In contrast to other VHL syndrome-associated tumors, only a handful of molecular studies have been published on RHs. It remains unclear whether VHL alterations alone drive RH tumorigenesis.

Whole-genome sequencing (WGS) was performed on germline- and RHs-derived DNA of five patients. Additionally, transcriptomes of four unaffected retinas and five choroid controls were compared with those of RH biopsies.

Heterozygous germline missense variants and copy number losses impacting VHL were identified. In all RH biopsies, mosaic loss of chromosome 3 was present, indicating the "second hit" in RHs is likely loss of the complete wild-type chromosome 3. Few additional somatic short nucleotide variants (SNVs) indels, or structural variants with deleterious potential were detected, suggesting that somatic changes are rare but not limited to the VHL gene region. RNA sequencing revealed reduced VHL expression in tumor tissue and downstream gene expression changes consistent with loss of VHL expression.

RHs have few somatic changes. Loss of chromosome 3 is likely the second hit in RHs with germline VHL alterations.

RHs are benign neoplasms with little somatic changes compared with other VHL-syndrome associated tumors. 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.