156 Small Terminal Deletions/Duplications and Alternative Lengthening of Telomeres are Co-Occur in IDH Mutation Only Gliomas

Abstract

Abstract INTRODUCTION Genetic variability is central to gliomagenesis. We recently showed that gliomas fall principally into five molecular groups. Further characterization may refine diagnosis and provide the basis for novel molecular therapeutic targets. METHODS We performed comprehensive copy number OncoScan array analysis and a 50-gene glioma panel on 148 formalin-fixed paraffin-embedded gliomas. Data validation was performed on the TCGA glioma dataset. Telomere-specific FISH was performed on 87 cases to detect alternative lengthening of telomeres (ALT). RESULTS >Small terminal deletions/duplications were found in 49 gliomas (33%) with 92% observed in IDH-only and TERT-only gliomas. There was increased prevalence of small terminal deletions/duplications in IDH-only relative to TERT-only gliomas (P < 0.0001). These terminal deletions/duplications were present in 20 of 28 (71%) ALT FISH positive cases, 7 of 24 (29%) ALT FISH negative cases, and 4 of 11 (36%) equivocal cases (P = 0.006). ALT FISH positivity was seen in 86% IDH-only tumors versus 11% in TERT-only and triple-positive lesions (P < 0.001). Among IDH-only gliomas, ATRX mutations were detected in 23 of 24 (96%) ALT FISH positive cases versus, 2 of 3 (67%) equivocal cases and was wild type in one ALT FISH negative case (P = 0.023). CONCLUSION The co-occurrence of small terminal alterations and ATRX mutations in IDH-only tumors raises the probability that copy number variations are the direct result of the ALT phenotype. We found a statistically significant association between the ALT phenotype, ATRX loss and small terminal alterations all of which occur in IDH-only tumors with near exclusivity. Alternatively, more than 80% of tumors with small terminal deletions and duplications were both ATRX mutated and ALT FISH positive. Thus, we conclude that the ALT phenotype results in small terminal copy number abnormalities in tumors with a permissive genetic milieu.