The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas

Nathalie Grandin (1) , Bruno Pereira (2) , Camille Cohen (3) , Pauline Billard (4) , Caroline Dehais (5) , Catherine Carpentier (6) , Ahmed Idbaih (6, 5) , Franck Bielle (6, 5) , François Ducray (7) , Dominique Figarella-Branger (8) , Jean-Yves Delattre (5, 6) , Marc Sanson (5, 6) , Patrick Lomonte (9) , Delphine Poncet (7) , Pierre Verrelle (10) , Michel Charbonneau (11)

1 GReD - Génétique, Reproduction et Développement
2 CHU Clermont-Ferrand
3 UPD5 Médecine - Université Paris Descartes - Faculté de Médecine
4 UNICAEN - Université de Caen Normandie
5 CHU Pitié-Salpêtrière [AP-HP]
6 ICM - Institut du Cerveau = Paris Brain Institute
7 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
8 INP - Institut de neurophysiopathologie
9 CGPhiMC - Centre de génétique et de physiologie moléculaire et cellulaire
10 CREaT - Cancer Resistance Exploring and Targeting
11 INRS-IAF - Institut Armand Frappier

All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative "C-circle" assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.

Mots clés: Secondary glioblastoma; ATRX loss of expression; Anaplastic astrocytoma; Alternative lengthening of telomeres; IDH1/2 mutations

Domaines: Sciences du Vivant [q-bio]; Cancer

Nathalie Grandin, Bruno Pereira, Camille Cohen, Pauline Billard, Caroline Dehais, et al.. The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas. Acta Neuropathologica Communications, 2019, 7 (1), ⟨10.1186/s40478-019-0833-0⟩. ⟨hal-02358653⟩