GCT-19. Toward understanding of the pathogenesis of central nervous system germ cell tumors

Central nervous system germ cell tumors (CNSGCT) are the most enigmatic brain tumors that arise predominantly in children and young adults. CNSGCTs are rare in Europe and North America, while they are rather common in East Asia. The genetic basis of the distinct regional prevalence is yet to be elucidated. The WHO Classification of Central Nervous System Tumours recognizes 6 subtypes of CNSGCT, however multiple subtypes are often present as a mixed tumor, and the subtype may change at the recurrence. In 2012, we organized the Intracranial Germ Cell Tumor Genome Analysis Consortium of Japan (iGCT Consortium) and have collected nearly 300 frozen tumor specimen and patients’ information for CNSGCT cases since then to comprehensively investigate the genomic/epigenomic mechanism of CNSGCT development. We found that alterations of the MAPK and/or PI3K pathways were present in approximately 50% of all subtypes of CNSGCTs, KIT mutations being the most common. Germinomas are characterized by global hypomethylation, indicating that their cell of origin may be primordial germ cells. Transcriptomic profiling suggested that germinomas and non-germinomatous germ cell tumors (NGGCTs) developed from the common cell of origin and then diverted at some stage. We also showed that components of mixed CNSGCT shared the identical somatic mutation while having distinct methylation profiles, supporting the common cell-of-origin theory. In this paper, we will present an overview of our investigation in the iGCT Consortium as well as some of the ongoing projects, single cell RNA sequencing among others.