Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

TLDR

Infant gliomas exhibit paradoxical clinical behavior—low‑grade tumors have higher mortality while high‑grade tumors fare better—and their biology remains poorly understood. The authors aim to delineate the genetic landscape of infant gliomas by conducting a comprehensive analysis of an international cohort, thereby identifying three clinically relevant subgroups. They performed a large‑scale genomic profiling of clinically annotated infant glioma samples from multiple centers to uncover recurrent driver alterations. The study identifies three distinct infant glioma subgroups: Group 1, cerebral‑hemisphere tumors with single ALK/ROS1/NTRK/MET alterations and intermediate prognosis; Group 2, hemispheric RAS/MAPK‑mutant tumors with excellent long‑term survival; and Group 3, midline RAS/MAPK‑mutant tumors that progress rapidly and are refractory to chemoradiation, underscoring the need for tailored therapies.

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.