Detection of telomeric maintenance mechanisms enabled classification of both typical and atypical glioma.

  • Major Finding: Detection of telomeric maintenance mechanisms enabled classification of both typical and atypical glioma.

  • Concept: An algorithm-based classification tool was developed and offers an option for liquid biopsy in glioma.

  • Impact: Use of this tool provides proof-of-concept for liquid biopsy to improve glioma diagnosis.

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Among the most common adult brain tumors are diffuse gliomas, which have a low median survival when they reach grade IV glioblastoma. Two main diagnostic biomarkers for these tumors are part of the telomeric maintenance mechanism (TMM) and include mutations in the TERT promoter and loss of ATRX, with phenotypic assessment of these potentially solving the currently common misdetection issues in ATRX alteration/loss observed using immunohistochemistry or next-generation sequencing. Furthermore, a lack of liquid biopsy for routine use in gliomas, which could provide significant clinical benefit, continues to remain a need within the field. Billard and colleagues developed a tool for TMM assessment using detection of C-circles (CC), which are partially double-stranded telomeric DNA circles that can be amplified using rolling circle amplification and quantified by telomere quantitative PCR. This assay was initially performed using both frozen and formalin-fixed paraffin-embedded (FFPE) tissue and indicated effectiveness in detection of both ATRX loss and TERT mutation with a selectivity of 100% and specificity of 99.3% for detection of these TMMs from 284 gliomas. Based on this success, an algorithm-based classification tool named “TeloDIAG” was developed that integrates TMM along with histologic grade and status of IDH1/2 which is commonly mutated in gliomas and associated with a favorable prognosis. Classification using this simple algorithm was concordant with currently used methods and was able to be used for the reclassification of gliomas with atypical molecular characteristics. Detection of CC in liquid biopsies from patients with glioma was also assessed from 206 blood samples and indicated CC was detectable in blood from IDH-mutant astrocytomas. Furthermore, this technique displayed an overall selectivity and specificity of 56.4% and 97% respectively. The development and validation of TeloDIAG suggests it may be an effective technique for the classification of gliomas with prognosis value and offers an application for IDH-mutant astrocytoma diagnosis and follow-up by liquid biopsy.

Billard P, Guerriau C, Carpentier C, Juillard F, Grandin N, Lomote P, et al. The TeloDIAG: how telomeric parameters can help in glioma rapid diagnosis and liquid biopsy approaches. Ann Oncol 2021 Oct 21 [Epub ahead of print].

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