Originally published as JCO Early Release 10.1200/JCO.2008.17.2833 on November 10 2008

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Polymorphism in the Microglial Cell-Mobilizing CX3CR1 Gene Is Associated With Survival in Patients With Glioblastoma

Mathieu Rodero, Yannick Marie, Mathieu Coudert, Emmeline Blondet, Karima Mokhtari, Audrey Rousseau, William Raoul, Catherine Carpentier, Florian Sennlaub, Philippe Deterre, Jean-Yves Delattre, Patrice Debré, Marc Sanson, Christophe Combadière

From Laboratoire d’Immunologie Cellulaire, L’Institut National de la Santé et de la Recherche Médicale U543; Laboratoire d’Immunologie Cellulaire and Unité de Biostatistique EA3974, Université Pierre et Marie Curie–Paris 06, Unité Mixte de Recherche_S543; Laboratoire de Biologie des Interactions Neurones et Glie, L’Institut National de la Santé et de la Recherche Médicale U711; Service de Neurologie Mazarin, Laboratoire de Neuropathologie Raymond Escourolle, and Laboratoire d’Immunologie, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière; and Laboratoire de Physiopathologie des Maladies Oculaires, Centre de Recherche des Cordeliers, L’Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche_S872, Paris, France

Corresponding author: M. Sanson, MD, PhD, INSERM U711, Fédération de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris CEDEX 13, France; e-mail: marc.sanson{at}psl.ap-hop-paris.fr

Purpose Few reliable prognostic molecular markers have been characterized for glioblastoma multiforme (GBM), considered the deadliest of human cancers. We hypothesized that genetic polymorphisms in chemokines and their receptors, which together control microglial cell mobilization, may influence survival.

Methods Distributions of one polymorphism of the chemokine CCL2 (–2518A<G) and two polymorphisms of the chemokine receptor CX3CR1 (termed V249I and T280M) were determined in a prospective series of 230 patients with GBM and correlated with overall survival. The replication study used data from a retrospective series of 106 additional patients with GBM. The extent of microglial cell infiltration was assessed by immunochemistry in 102 tumor specimens.

Results Survival analysis showed that the common CX3CR1-I249 allele was an independent favorable prognostic factor in both groups, prospective and retrospective, with hazard ratios of 0.619 (95% CI, 0.451 to 0.850; P = .0031) and 0.354 (95% CI, 0.217 to 0.580; P < .0001), respectively. This beneficial effect was observed only in patients who underwent surgery. Patients with only this CX3CR1-I249 allele had a substantially longer mean survival (23.5 v 14.1 months; P < .0001). The CCL2-2518G allele was not associated with patient survival. Immunohistochemical analysis of primary tumor biopsies showed that the common CX3CR1 variant allele was associated with reduced microglial cell infiltration.

Conclusion The common CX3CR1 allelic variant was associated with increased GBM survival and with reduced tumor infiltration by microglia. The CX3CR1 polymorphism does not seem to be a risk factor for GBM but may prove useful in predicting survival.

published online ahead of print at www.jco.org on November 10, 2008.

Supported in part by grants from the Institut du Cancer (INCA 2005), the Canceropôle-Ile de France, the Agence Nationale de la Recherche "Cardiovasculaire, Obésité et Diabète" (Grant No. AO5088DS), and the Centre de Resources de Modèles Expérimentaux de Cancer. M.R. was a recipient of a fellowship from Canceropôle-Ile de France. W.R. was a recipient of Agence Nationale de la Recherche "Blanc" (Grant No. AO5120DD).

M.S. and C. Combadière contributed equally to this work.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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