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

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.

Pediatric low-grade glioma in the era of molecular diagnostics

“…These alterations are most commonly fusion events that result in ectopic expression of the ALK fusion protein [6]. This results in up-regulation of the RAS/MAPK and PI3K/AKT/mTOR pathways [73,143]. Despite the frequency of ALK alterations in pediatric cancer, reports of its presence in glioma are rare and often exist in isolated case reports [1,147,152].…”

“…Despite the frequency of ALK alterations in pediatric cancer, reports of its presence in glioma are rare and often exist in isolated case reports [1,147,152]. The most frequently reported alterations are CCDC88A-ALK and PPP1CB-ALK, both resultant fusions from a larger chromothripsis event [1,73,147,152]. Recently, ALK alterations were shown to form a unique clinical subgroup of infantile glioma that require would likely benefit from a refined treatment approach [73].…”

“…The most frequently reported alterations are CCDC88A-ALK and PPP1CB-ALK, both resultant fusions from a larger chromothripsis event [1,73,147,152]. Recently, ALK alterations were shown to form a unique clinical subgroup of infantile glioma that require would likely benefit from a refined treatment approach [73].…”

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…Additional molecular features of this class are not currently known . A possible relation of this methylation class to infantile hemispheric gliomas with ALK , ROS1 , NTRK1/2/3, or MET alterations requires further investigation .…”

“…Lastly, gliomas with malignant histological features includes a methylation class where further characterisation is pending and that has been provisionally named ‘infantile hemispheric glioma’ . A relation of this methylation class to the recently described infantile hemispheric gliomas driven by alterations of either ALK , ROS1 , NTRK1/2/3 or MET seems likely but has to be further substantiated. A central role of DNA methylation profiling for gliomas with malignant histological features is the validation of diagnosis and in particular the exclusion of a lower grade lesion in ‘disguise’.…”