Abstract
BACKGROUND: Infants (< 1 year of age) with low (LGG)- and high-grade gliomas (HGG) have paradoxical survival outcomes when compared with older children. The association between tumor grade and outcome is less predictable, as is the response to classic LGG and HGG treatment. The clinical and molecular factors underlying these differences remain poorly characterized. METHODS: Multi-institutional collaborative retrospective study. We integrated genetic testing with morphologic characterization and detailed clinical outcome of 142 patients diagnosed with gliomas (WHO I-IV) in the first year of life with follow-up data spanning three decades (1985–2017). Novel oncofusions were further validated in vitro and in vivo. RESULTS: Infant gliomas comprise three unique groups of tumors; Group 1 are hemispheric receptor tyrosine kinase (RTK)-driven tumors, mostly but not exclusively HGG, and include gliomas harboring unreported ALK, ROS1 and NTRK1/2/3 fusions, analogous to alterations observed in adult tumors, such as lung cancer. Unlike in adult cancers, these alterations were often the only genetic drivers present. iNHA cells transduced with the most common ALK fusions were tumorigenic in vivo and susceptible to targeted agents. Group 2 are hemispheric Ras/MAPK-driven tumors, which show excellent long-term survival requiring minimal interventions post-surgery. Group 3 are midline Ras/MAPK-driven gliomas, enriched for LGG (optic pathway hypothalamic glioma) harboring BRAF alterations and with a surprisingly poor outcome. CONCLUSION: Most infant LGG and HGG showed single and actionable molecular drivers (BRAF, FGFR, ALK, ROS1, NTRK and MET), including novel oncofusions that are observed throughout pathological grades. This study broadens our understanding of cancers early in life and highlights the need for a change to clinical practice: early biopsy, routine molecular characterization, and the evaluation of targeted inhibitors in their treatment.