ROS1 alterations as a potential driver of gliomas in infant, pediatric, and adult patients

Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1-fusion positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1-fusion gliomas along with the characterization and meta-analysis of new and published cases. The cohort of 32 new and 58 published cases was divided into three age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histological features. GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and ten other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH-wild-type glioblastoma, including +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and hemispheric location appeared more aggressive than tumors with lower-grade histology or those in non-hemispheric locations. In conclusion, this study is the largest-to-date to characterize the clinicopathological and molecular signatures of ROS1-fusion positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or co-driver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.