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Telomere Profiling: Toward Glioblastoma Personalized Medicine

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Abstract

Despite a standard of care combining surgery, radiotherapy (RT), and temozolomide chemotherapy, the average overall survival (OS) of glioblastoma patients is only 15 months, and even far lower when the patient cannot benefit from this combination. Therefore, there is a strong need for new treatments, such as new irradiation techniques. Against this background, carbon ion hadrontherapy, a new kind of irradiation, leads to a greater biological response of the tumor, while minimizing adverse effects on healthy tissues in comparison with RT. As carbon ion hadrontherapy is restricted to RT-resistant patients, photon irradiation resistance biomarkers are needed. Long telomeres and high telomerase activity have been widely associated with photon radioresistance in other cancers. Moreover, telomere protection, telomere function, and telomere length (TL) also depend on the shelterin protein complex (TRF1, TRF2, TPP1, POT1, TIN2, and hRAP1). We thus decided to evaluate an enlarged telomeric status (TL, telomerase catalytic subunit, and the shelterin component expression level) as a potential radioresistance biomarker in vitro using cellular models and ex vivo using patient tumor biopsies. In addition, nothing was known about the role of telomeres in carbon ion response. We thus evaluated telomeric status after both types of irradiation. We report here a significant correlation between TL and the basal POT1 expression level and photon radioresistance, in vitro, and a significant increase in the OS of patients with long telomeres or a high POT1 level, in vivo. POT1 expression was predictive of patient response irrespective of the TL. Strikingly, these correlations were lost, in vitro, when considering carbon irradiation. We thus propose (1) a model of the implications of telomeric damage in the cell response to both types of irradiation and (2) assessment of the POT1 expression level and TL using patient tumor biopsies to identify radioresistant patients who could benefit from carbon hadrontherapy.

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Acknowledgments

This work was supported by “La Ligue Nationale contre le Cancer” (comité de la Saône), the “Association pour la Recherche contre le Cancer” (ARC), the “Association des Neuro-Oncologues d’Expression Française” (ANOCEF), and Geron Corp. We thank Mrs. Helen Morrin and Mr. Martin McFarlane of The Cancer Society Tissue Bank, The University of Otago Christchurch (New Zealand) for the glioma tissue samples and related information. We thank the GRRAAL (Gliomas Radiobiology Rhône-Alpes Auvergne Labs) project for sharing the GBM-derived cell lines, Guillaume Belz for his valuable help in “R” manipulation, and Sergei Gryaznov for his accurate corrections. Pr. Rodriguez-Lafrasse Laboratory is part of the Labex PRIMES (“Physique Radiobiologie Imagerie Médicale et Simulation”) and is supported by the PRRH (Programme Régional de Recherches en Hadronthérapie).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. EMR3738, Cellular and Molecular Radiobiology Laboratory, Medicine Faculty, Lyon 1 University, 69921, Oullins Cedex 12, France

    Sylvain Ferrandon, Paul Saultier, Priscillia Battiston-Montagne, Gersende Alphonse, Claire Rodriguez-Lafrasse & Delphine Poncet

  2. Université Claude Bernard Lyon 1, 69622, Lyon, France

    Sylvain Ferrandon, Paul Saultier, Priscillia Battiston-Montagne, Jérôme Honnorat, Claire Rodriguez-Lafrasse & Delphine Poncet

  3. Biochemistry Department, Transfer and Molecular Oncology Unit, Lyon Sud Hospital, Hospices Civils de Lyon, 69495, Pierre Bénite, Lyon, France

    Julien Carras, Claire Rodriguez-Lafrasse & Delphine Poncet

  4. Lyon Sud Hospital, Hospices Civils de Lyon, 69495, Pierre Bénite, Lyon, France

    Gersende Alphonse

  5. Nuclear Physics Institute of Lyon, 69622, Villeurbanne, France

    Michael Beuve

  6. Lyon Neuroscience Research Center, INSERM U1028/CNRS UMR, 5292, Lyon, France

    Céline Malleval & Jérôme Honnorat

  7. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Tania Slatter, Noelyn Hung & Janice Royds

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  1. Sylvain Ferrandon
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Correspondence to Delphine Poncet.

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Ferrandon, S., Saultier, P., Carras, J. et al. Telomere Profiling: Toward Glioblastoma Personalized Medicine. Mol Neurobiol 47, 64–76 (2013). https://doi.org/10.1007/s12035-012-8363-9

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