ORIGINAL ARTICLE The TeloDIAG: how telomeric parameters can help in glioma rapid diagnosis and liquid biopsy approaches P. Billard 1,2 , C. Guerriau 1 , C. Carpentier 3 , F. Juillard 4 , N. Grandin 5 , P. Lomonte 4 , P. Kantapareddy 6 , N. Dufay 6 , M. Barritault 1 , R. Rimokh 7 , P. Verrelle 5 , D. Maucort-Boulch 8 , D. Figarella-Branger 9,10 , F. Ducray 7,11 , C. Dehais 12 , M. Charbonneau 5 , D. Meyronet 1,7 & D. A. Poncet 1,2* , the POLA network 1 Institut de Pathologie Est, Hospices Civils de Lyon, Lyon; 2 Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène (INMG), Neuron-Muscle Interaction Team, Lyon; 3 Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris; 4 Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), Team Chromatin Dynamics, Nuclear Domains, Virus, Lyon; 5 GReD Institute, CNRS UMR6293, INSERM U1103, University Clermont Auvergne, Faculty of Medicine, Clermont-Ferrand; 6 Hospices Civils de Lyon, Lyon; 7 Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon; 8 Biostatistics and Bioinformatics department of the Hospices Civils de Lyon, Lyon; 9 Aix-Marseille Univ, CNRS, INP, Inst. Neurophysiopathol, Marseille; 10 AP-HM, CHU Timone, Service d’Anatomie Pathologique et de Neuropathologie, Centre de Ressources Biologiques CRB-TBM, Marseille; 11 Hospices Civils de Lyon, Hôpital Neurologique, Bron; 12 Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié SalpêtrièredCharles Foix, Service de Neurologie 2-Mazarin, Paris, France Available online 22 October 2021 Background: 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. Materials and methods: The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. Results: We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n ¼ 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 ALTþ 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 ¼ 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 ¼ 206 gliomas and 30 healthy donors). Conclusion: The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy. Key words: glioma, telomere, C-circle, alternative lengthening of telomeres, liquid biopsy, diagnosis INTRODUCTION Diffuse gliomas (grade II-IV) are the most frequent primary adult brain tumors; the patient median survival ranges from 10 to 15 years (for grades II-III) but reaches only 15 months for glioblastoma (GBM; grade IV). Their diagnosis de- termines therapeutic management, and owing to the complexity of immunohistological approaches, the World Health Organization (WHO) classification has recently inte- grated numerous molecular markers (2016). 1 These include the mutations of the isocitrate dehydrogenases 1 and 2 genes (IDHmt), of the histone H3.3- and H3.1-encoding genes (G34R/V, K27M), and 1p19q codeletion (1p19q loss), 1 hence defining the following classes of diffuse gli- omas: (i) oligodendroglioma (OD) (IDHmt, 1p19q loss, grades II-III), (ii) IDHmt low-grade astrocytoma (LGA) *Correspondence to: Dr Delphine A. Poncet, Institut de Pathologie Est, Unité de Biopathologie moléculaire, Hospices Civils de Lyon, 59 Boulevard Pinel, 68500 Bron, France. Tel: þ33-(0)-4-27855734 E-mail: [email protected] (D. A. Poncet). 0923-7534/© 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved. 1608 https://doi.org/10.1016/j.annonc.2021.09.004 Volume 32 - Issue 12 - 2021
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