PTHP-06. Molecular Mechanisms and Developmental Pathways of CNS Germ Cell Tumors Elucidated through Whole Genome Analysis

BACKGROUND Genomic alterations in germ cell tumors (GCTs) have been identified in the RTK, MAPK, and PI3K pathways through whole exome sequencing, with a prevalence of 71% in germinomas but only 33% in non-germinomas GCTs (NGGCTs). Despite evolution in treatment, GCTs present therapeutic challenges and lack molecularly targeted strategies. METHODS Whole genome sequencing was performed on 71 cases (37 germinomas and 34 NGGCTs) from the iGCT Genome Analysis Consortium and the Japan Children’s Cancer Group. RESULTS Putative driver mutations were identified in 83% of tumors, primarily involving RAS/MAPK followed by mTOR/Akt pathways. Germinomas exhibited a higher mutation frequency than NGGCTs (84% vs 62%), with KIT enriched in germinomas and USP28 in NGGCTs. All USP28 alterations were bi-allelic and highly specific to CNS GCTs, with only one diffuse midline glioma out of 1448 cases of pediatric cancers affected. Variant allele frequency and clonal analyses revealed that these mutations occurred early, preceding copy number alterations. Germline analysis identified Kleinfelter or Down syndrome in 5.6% of cases, particularly in NGGCTs lacking other alterations. CONCLUSION Many cases exhibited driver mutations present in major clonal populations and could serve as therapeutic targets. There were notable differences based on histological type, with a diverse range of single nucleotide variants/structural variants observed in NGGCTs. A timeline of tumorigenesis from SNVs/SVs to copy number abnormalities was observed. The utility of understanding germline variants was also implicated in the pathogenesis.