Abstract
INTRODUCTION
Hemangioblastomas (HBs) are benign central nervous system (CNS) neoplasms that present as sporadic, isolated lesions or as a subset of CNS lesions in von Hippel-Lindau (VHL) disease. VHL disease caused by a germline mutation of VHL on chromosome 3 predisposes individuals to multi-organ tumors, including clear cell renal cell carcinomas (ccRCCs), as well as HBs. HBs have not been analyzed in detail regarding genetic and epigenetic alterations as much as ccRCCs.
METHODS
Genetic and epigenetic alterations were comprehensively analyzed in 11 VHL disease-related HBs and 21 sporadic ones.
RESULTS
Using direct sequencing, target deep sequencing, multiplex ligation-dependent probe amplification assays, VHL alterations were detected in 100% and 62% of VHL-related and sporadic HBs, respectively. Using data from single nucleotide polymorphism arrays, the almost similar ratios of VHL-related and sporadic HBs were found loss of heterogyzosity (LOH) on chromosome 3 (64% and 57%, respectively). VHL premotor hypermethylation was detected only in sporadic HBs (33%). The rate of biallelic VHL inactivation among VHL-related and sporadic HBs was 64% and 52%, respectively. No significant mutation of PBRM1,BAP1,SETD2, which are novel candidate genes that may be causative for ccRCCs, was detected in HBs by using target deep sequencing. No HB of CIMP (CpG island methylator phenotype), which was known to be detected in a subset of ccRCCs, was detected by using an Illumina Infinium 450K methylation chip.
CONCLUSION
Although biallelic inactivation of VHL is a dominant mechanism in the pathogenesis of HBs, as well as ccRCCs, other unknown mechanisms different from ccRCCs may also be involved in the pathogenesis of HBs.