The TeloDIAG: how telomeric parameters can help in glioma rapid diagnosis and liquid biopsy approaches

In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations. The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors). The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy. •CC is a simple and cost-effective assay, able to overcome the misdetection of alterations in TERT and ATRX.•The ‘TeloDIAG’ is a rapid diagnostic tool for glioma based on CC, IDH status, and histological grading.•A third of glioma discordant for histo-molecular markers are classed differently by the TeloDIAG, with prognosis value.•The activation of the ALT mechanism tends to be of good prognosis in IDHwt gliomas.•Outstandingly in glioma, a circulating marker has been retrieved with a sensitivity of 56% and an excellent specificity.