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

Abstract 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.

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Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.1063
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

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

Takako Yoshioka, Takaaki Sato, Yuko Matsushita, Yuichi Hirose et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

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

Takako Yoshioka, Takaaki Sato, Yuko Matsushita, Yuichi Hirose, Akitake Mukasa, Junko Hirato, Shota Kato, Yuichi Shiraishi, Kenichi Yoshida, Eiji Sugihara, Ryo Nishikawa, Tatsuhiro Shibata, Tomonari Suzuki, Masayuki Kanamori, Akihide Kondo, Akio Asai, Kazuhiko Sugiyama, Hirokazu Takami, Motoo Nagane, Yuki Yamagishi, Motohiro Kato, Koichi Ichimura, Toshihiro Kumabe, Miho Kato, Hajime Okita
article en

Abstract

Abstract 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.

Neuro-OncologyVol. 27(Supplement_5)
Hiroshima University (JP), Kansai Medical University (JP), University of Tsukuba (JP), Hiroshima University of Economics (JP), Kyorin University (JP), Tohoku University (JP), Keio University (JP), Juntendo University (JP), University of Tokyo Hospital (JP), Kumamoto University Hospital (JP), Gunma Museum of Natural History (JP), Fujita Health University Hospital (JP), National Center For Child Health and Development (JP), Saitama International Medical Center (JP), National Cancer Research Institute (GB), Kitasato University (JP), Saitama Medical University (JP)
Openalex Percentile: Top 52%
Glioma Diagnosis and Treatment
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