GC-01ELUCIDATION OF PATHOGENESIS IN INTRACRANIAL GERM CELL TUMORS BASED ON A GENOME-WIDE METHYLATION STUDY

OBJECTIVE: Although “germ cell theory” that primordial germ cells (PGCs) might be a cell of origin of intracranial germ cell tumors (iGCTs) is now widely accepted, the nature of this heterogeneous tumor remains largely unknown. To elucidate the pathogenesis of iGCT, we are currently conducting a comprehensive methylation analysis. METHODS: Bisulfite-modified DNA of 58 iGCTs from frozen tissues (20 germinomas, and 38 NGGCTs), and 4 mixed-GCTs from FFPE tissues after microdissection (germinoma and the other histological component) were subjected to a genome-wide methylation analysis using HumanMethylation450 BeadChip, which were subclassified by an unsupervised hierarchical clustering. The DNA methylation levels of iGCTs were compared to those of mice PGCs in the published data. In mixed-GCTs after microdissection, mutation status of each component was analyzed by Sanger sequencing. RESULTS: According to the methylation profiles, iGCTs were subclassified into the following 3 groups; global lower methylation (GLM), partial lower methylation (PLM) and higher methylation (HM). Pure germinomas showed a prominent hypomethylation pattern clustered to GLM, which is a unique epigenomic feature distinguishable from NGGCTs. DNA methylation profiles in pure germinoma are similar to those in mice PGCs at E10.5. Mixed-GCTs show different methylation, but common mutation profiles between germinoma and the other histological component. CONCLUSION: We conclude that intracranial germinoma might originate from the migration phase of PGC, but the other subtypes of GCTs might not. We further propose that mutation is earlier event than methylation in the pathogenesis of iGCTs.