gms | German Medical Science

Objective: Hemangioblastomas (HBs) of the central nervous system are rare tumors and occur sporadically or as a manifestation of von Hippel-Lindau (vHL) disease. Despite their benign nature, the clinical course is variable. Therefore, a better knowledge of molecular factors involved in HB tumor biology may aid in identifying patients at risk for recurrence.

Methods: DNA methylation profiling was performed in a series of 47 HBs. Clinical data were retrieved retrospectively from medical records. Histologic subtypes (reticular and cellular) were extracted from the pathology reports. All samples were analyzed on the Infinium Methylation EPIC BeadChip to determine the methylation status of ca. 850.000 CpG-Sites and were performed in R 4.0.3 and 4.10. After preprocessing with minfi and quality checks, the most variable CpG-Sites were selected by standard deviation, and dimensionality reduction was performed with tSNE and UMAP. Consensus clustering was performed using the COLA-Package to determine the number of subgroups.

Results: The series comprised 29 males and 18 females, including 28 individuals with vHL disease. Median age of patients with vHL associated tumors was significantly younger (39.6 vs. 55.7 years, p= 0.00048, t-test). Thirty tumors occurred in the cerebellum, 8 in the brainstem, while 8 HBs were spinal. Dimensionality reduction and unsupervised clustering of DNA methylation data separated the tumors into two distinct and stable subgroups (30 group 1 and 17 group 2). The two subgroups were associated with tumor location and the histologic subtype (p=0.00000001, Chi-square test). Reference-free deconvolution revealed four latent methylation components, two of which were associated with an endothelial signature.

Conclusion: Results indicate DNA methylation might play a role in the biology of HBs. No difference could be determined between sporadic and vHL-associated HBs as well as cyst-forming vs. non-cyst-forming HBs. There is strong evidence that cerebellar HBs significantly differ from non-cerebellar hemangioblastoma in the spinal column and brainstem. Further examination of latent methylation components of a larger cohort is warranted.