TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations

• Published in: Acta neuropathologica communications Vol. 6; no. 1; pp. 106 - 6
• Main Authors: Williams, Erik A., Miller, Julie J., Tummala, Shilpa S., Penson, Tristan, Iafrate, A. John, Juratli, Tareq A., Cahill, Daniel P.
• Format: Journal Article
• Language: English
• Published: London BioMed Central 17.10.2018; BioMed Central Ltd; BMC
• Subjects: BAF complex; Biomedical and Life Sciences; Biomedicine; Brain cancer; Comparative analysis; Diagnosis; Genes; Genetic aspects; Glioma; Gliomas; H3F3A; IDH1; Medical prognosis; Mutation; Nervous system; Neurology; Neurosciences; Pathology; PI3K pathway; TERT promoter; Tumors; Cerebellum; Glioma; IDH1; H3F3A; BAF complex; PI3K pathway; TERT promoter
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-018-0613-2

TERT promoter ( TERT p) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma ( IDH -wt GBM). Here, we characterized the subset of IDH -wt GBMs that do not have TERT p mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH -wt GBMs, after excluding 11 IDH -mutant cases and one H3F3A - mutant case. Within the IDH -wt cases, 16 cases (14.7%) were TERT p wild-type ( TERT p-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERT p-wt GBMs, were significantly younger at first diagnosis (53.2 years vs. 60.7 years, p  = 0.0096), and were more frequently found to have cerebellar location ( p  = 0.0027). Notably, 9 of 16 (56%) of TERT p-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERT p-mutant GBMs harbored these alterations ( p  = 0.0018). As expected, 8/16 (50%) of TERT p-wt GBMs harbored mutations in the BAF complex gene family ( ATRX, SMARCA4 , SMARCB1 , and ARID1A ), compared with only 8/93 (9%) of TERT p-mutant GBMs ( p  = 0.0003). Mutations in BAF complex and PI3K pathway genes co-occurred more frequently in TERT p-wt GBMs ( p  = 0.0002), an association that has been observed in other cancers, suggesting a functional interaction indicative of a distinct pathway of gliomagenesis. Overall, our finding highlights heterogeneity within WHO-defined IDH wild-type GBMs and enrichment of the TERT p-wt subset for BAF/PI3K-altered tumors, potentially comprising a distinct clinical subtype of gliomas.