HG-71: ULTRA-SENSITIVE DETECTION OF HOTSPOT MUTATIONS IN PEDIATRIC THALAMIC TUMOURS TO REVEAL NEGATIVE PROGNOSTIC MARKERS

Pediatric gliomas are the most commonly diagnosed brain cancer in children. Despite accounting for only 5% of pediatric brain neoplasms, gliomas arising in the thalamus present a significant challenge for treating physicians. We collected a population-based cohort of 66 radiologically confirmed thalamic tumours with long-term follow-up. No bi-thalamic cases were included. On central review, the cohort consisted of 43 low grade astrocytomas (LGA) and 23 high grade astrocytomas (HGA). Genomic alterations were characterized using newly optimized digital droplet and nanoString assays. Five (12%) LGAs and eleven (48%) HGAs tested positive for H3-K27M. Kaplan-Meier analysis revealed significantly worse survival of thalamic glioma patients harbouring the H3-K27M mutation versus wild type samples (log rank p < 0.001) with a median survival of 1.02 vs. 9.12 years, respectively. When separated by histologic grade, H3-K27M status remained a prognostic marker in LGA (p < 0.0001), but failed to maintain statistical significance in the HGA cohort (p = 0.0599). BRAF-V600E and BRAF-Fusion events were detected in 10 and 14 patients respectively. Interestingly, tumours with BRAF-fusion events showed robust survival, with no patients succumbing to their disease (median follow-up 11.5 years). Multivariate analysis demonstrated H3-K27M status and histology to be the most significant predictors of survival with hazard ratios of 8.7 and 12.7 (P < 0.001), respectively. This work substantiates the need for H3-K27M testing in conjunction with histological grading in dictating appropriate diagnosis. Further, we show that low grade malignancies harbouring H3-K27M mutations represent a newly identified subset of thalamic tumours with a unique survival pattern when compared to low grade H3-WT cases.