- Patients in the TERT promoter wild-type (TERTp-wt) subgroup of IDH wild-type glioblastoma were significantly younger at diagnosis than patients with TERTp mutant glioblastoma
- TERTp-wt status significantly correlated with cerebellar location of the primary tumor
- There were strong correlations between TERTp-wt status and mutations in the PI3K pathway, ATRX and the BAF complex gene family
- BAF complex and PI3K pathway gene mutations tended to co-occur, suggesting a distinct pathogenesis of TERTp-wt tumors
In 2016, the World Health Organization updated its diagnostic criteria for central nervous system tumors to include molecular markers. Glioblastoma was divided according to the status of the isocitrate dehydrogenase (IDH) gene: IDH mutant and IDH wild-type.
The IDH wild-type subgroup is quite heterogeneous. This is important because most adult grade IV glioblastomas fall into that category, and additional subclassification could lead to better management.
Building on previous research, Tareq A. Juratli, MD, a research fellow in Neurosurgery, Daniel P. Cahill, MD, PhD, a neurosurgeon at Massachusetts General Hospital, and colleagues have identified a new type of glioblastoma. In Acta Neuropathologica Communications, they say the telomerase reverse transcriptase (TERT) promoter wild-type subgroup of IDH wild-type glioblastoma has distinct clinical features and a distinct molecular profile.
The researchers genotyped tumor specimens from 109 patients using SNaPshot, a broad panel that targets genetic loci frequently mutated in certain cancer genes, including TERT promoter and IDH1/2. All told, 93 tumors had genetic alterations in TERT and 16 were TERT promoter wild-type (TERTp-wt).
Patient Age and Tumor Location
On average, the research group found the patients with TERTp-wt glioblastomas were significantly younger at diagnosis than those with TERTp mutant tumors (53 vs 61 years, P =.01) and significantly older than patients with IDH mutant glioblastomas (53 vs 39 years, P=.004).
The location of the primary tumor also differed. In the TERTp mutant group, the tumors were exclusively located supratentorially (n=91) or thalamic/midline (n=2), with none found in the cerebellum. In contrast, in the TERTp-wt group, three of the 16 tumors were found in a cerebellar site, and TERTp-wt status significantly correlated with cerebellar location (P=.003).
The researchers also found some significant genetic differences between TERTp-wt and TERTp mutant glioblastomas:
- 56% of TERTp-wt tumors contained a mutation targeting the PI3K pathway, compared with 17% of TERTp mutant tumors
- Sequencing showed ATRX mutations in 37.5% of TERTp-wt tumors, but only 6.5% of TERTp mutant tumors; immunohistochemistry showed ATRX mutations in 31% and 0%, respectively
- Even after excluding ATRX, 19% of TERTp-wt tumors harbored mutations in the BAF complex gene family, compared with only 2% of TERTp mutant tumors
Furthermore, mutations in the BAF complex and mutations in the PI3K pathway co-occurred significantly more often in TERTp-wt tumors (31%) than in TERTp mutant tumors (1%). According to the researchers, this association suggests a functional interaction underlying a distinct pathway of gliomagenesis for TERTp-wt tumors.
The researchers believe their findings will eventually have implications for the use of targeted therapy in patients with TERTp-wt tumors. For now, they say, a definite conclusion is that TERTp mutant and TERTp-wt tumors should be analyzed separately in future clinical studies because they probably represent distinct subclasses of glioblastoma.
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