Abstract

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Highlights

  • Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome

  • We find that infant gliomas comprise three main subgroups: (1) hemispheric receptor tyrosine kinase (RTK)-driven tumors, including ALK, ROS1, NTRK, and MET fusions, which are enriched for HGG and have an intermediate clinical outcome, (2) hemispheric RAS/MAPK-driven tumors, which show excellent long-term survival with minimal clinical intervention post-surgery, and (3) midline RAS/ MAPK-driven tumors, which are enriched for LGG with BRAF alterations and have a relatively poor outcome even after conventional chemotherapeutic approaches

  • Young children with LGG have a worse survival when compared with older children[13,18,19] and to clarify whether this effect can be ascribed to the demographic

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Summary

Introduction

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. We find that infant gliomas comprise three main subgroups: (1) hemispheric receptor tyrosine kinase (RTK)-driven tumors, including ALK, ROS1, NTRK, and MET fusions, which are enriched for HGG and have an intermediate clinical outcome, (2) hemispheric RAS/MAPK-driven tumors, which show excellent long-term survival with minimal clinical intervention post-surgery, and (3) midline RAS/ MAPK-driven tumors, which are enriched for LGG with BRAF alterations and have a relatively poor outcome even after conventional chemotherapeutic approaches. This suggests that updated clinical approaches are required to modernize treatment and improve the outcome of these infants

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