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VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab

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Abstract

Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5′ untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.

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Abbreviations

VEGFA:

(Vascular endothelial factor A)

OS:

(Overall survival)

PFS:

(Progression free survival)

W.H.O.:

(World Health Organization)

KPS:

(Karnofsky performance status)

SNP:

(Single nucleotide polymorphism)

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Acknowledgments

Work supported by a Grant from the Institut National du Cancer (INCa; Angiogli- RAFc0209). A.L. Di Stefano received an investigator fellowship from PRIN 2010ZESJWN_008. The research leading to these results has received funding from the program “investissements d’avenir” ANR-10-IAIHU-06. The authors are indebted to Alexandru Agachi for English Editing.

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Author information

Authors and Affiliations

  1. UMPC Univ Paris VI, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, INSERM U 1127, CNRS, UMR 7225; GH Pitié-Salpêtrièr, Sorbonne Universités, 75013, Paris, France

    Anna Luisa Di Stefano, Marianne Labussiere, Jaime Gallego-Perez-Larraya, Blandine Boisselier, Francois Ducray, Caroline Cheneau, Amithys Rahimian, Khe Hoang-Xuan, Jean Yves Delattre, Karima Mokhtari & Marc Sanson

  2. Service de Neurologie 2, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

    Anna Luisa Di Stefano, Patrizia Farina, Stefania Cuzzubbo, Jaime Gallego-Perez-Larraya, Khe Hoang-Xuan, Jean Yves Delattre & Marc Sanson

  3. National Neurological Institute C. Mondino, DBBS, University of Pavia, Pavia, 27100, Italy

    Anna Luisa Di Stefano & Arrigo Moglia

  4. Department of Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology - IRCCS, Padua, Italy

    Giuseppe Lombardi & Patrizia Farina

  5. Neuro-oncology Unit, National Neurological Institute C. Besta, Milan, Italy

    Marica Eoli, Donata Bianchessi, Stefania Cuzzubbo & Gaetano Finocchiaro

  6. Deptartment Radiotherapy, University Hospital of Pisa, Pisa, Italy

    Francesco Pasqualetti

  7. Department of Neurology, Clinic of the University of Navarra, University of Navarra School of Medicine, Pamplona, Spain

    Jaime Gallego-Perez-Larraya

  8. Institut du Cerveau et de la Moelle épinière (ICM), Plateforme de Génotypage Séquençage, 75013, Paris, France

    Yannick Marie

  9. Onconeurothèque, 75013, Paris, France

    Amithys Rahimian, Jean Yves Delattre, Karima Mokhtari & Marc Sanson

  10. Laboratoire de Neuropathologie R. Escourolle, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

    Karima Mokhtari

  11. Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris Cedex 13, France

    Marc Sanson

Authors
  1. Anna Luisa Di Stefano
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  2. Marianne Labussiere
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  3. Giuseppe Lombardi
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  4. Marica Eoli
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  5. Donata Bianchessi
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  6. Francesco Pasqualetti
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  7. Patrizia Farina
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  8. Stefania Cuzzubbo
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  9. Jaime Gallego-Perez-Larraya
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  10. Blandine Boisselier
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  11. Francois Ducray
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  12. Caroline Cheneau
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  13. Arrigo Moglia
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  14. Gaetano Finocchiaro
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  15. Yannick Marie
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  16. Amithys Rahimian
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  17. Khe Hoang-Xuan
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  18. Jean Yves Delattre
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  19. Karima Mokhtari
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  20. Marc Sanson
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Corresponding author

Correspondence to Marc Sanson.

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Di Stefano, A.L., Labussiere, M., Lombardi, G. et al. VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab. J Neurooncol 121, 499–504 (2015). https://doi.org/10.1007/s11060-014-1677-x

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  • DOI: https://doi.org/10.1007/s11060-014-1677-x

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