title: Differential gene methylation in paired glioblastomas suggests a role of immune response pathways in tumor progression.
abstract: DNA and histone methylation are post-transcriptional modifications that have been recently described in gliomas. Indeed, glioma CpG island hypermethylated phenotype has been identified as prognostic biomarker and as a surrogate marker of IDH1/2 mutations. However, the role of DNA methylation in glioblastoma progression is unknown. We sought to analyze DNA methylation levels in paired (initial and recurrent) primary glioblastoma samples to identify candidate pathways that may prone to glioblastoma progression. We have analyzed 12 samples (5 paired samples, two of them with three surgeries) using methylation arrays. We have analyzed differential methylation at probe and at gene region level. Finally, pathway analysis has been performed using differentially methylated regions. All analysis has been performed with R and Bioconductor packages. Mean methylation level at initial sample compared to recurrence was strongly positively correlated (R(2) = 0.98). There was no differentially methylation at probe level. However, at gene level 3080 regions were differentially methylated. Interestingly, pathways analysis showed that the most differentially methylated genes are involved in cellular response to macrophage colony-stimulating factor stimulus (GO:0036006). Methylation levels were strongly conserved when comparing initial to recurrence in primary glioblastomas. Interestingly, differentially methylated pathway analysis suggests that a modulation of methylation in immune response genes may play a role in glioblastoma progression. Further studies are needed to validate the role of methylation of glioblastoma immune response genes in tumor progression.
authors.affiliation: Inserm, U 1127, 75013, Paris, France. agusti.alentorn@gmail.com.|CNRS, UMR 7225, 75013, Paris, France. agusti.alentorn@gmail.com.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013, Paris, France. agusti.alentorn@gmail.com.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France. agusti.alentorn@gmail.com.|Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France. agusti.alentorn@gmail.com.
authors.forename: Agustí
authors.initials: A
authors.lastname: Alentorn
authors.affiliation: Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Durán-Peña
authors.affiliation: Institut-Hospitalo-Universitaire Institut du Cerveau et de la Moelle épinière (IHU-ICM), Plateforme de Bioinformatique/Biostatistique, Paris, France.
authors.forename: Andigoni
authors.initials: A
authors.lastname: Malousi
authors.affiliation: Institut du Cerveau et de la Moelle épinière (ICM), INSERM U 1127, CNRS, UMR 7225 and Plateforme de séquençage et génotypage, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.affiliation: Inserm, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.|AP-HP, Hôpital Universitaire la Pitié Salpêtrière, Service de Neuropathologie, 75013, Paris, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: Inserm, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.|Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: Inserm, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.|Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Khê
authors.initials: K
authors.lastname: Hoang-Xuan
authors.affiliation: Inserm, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.|Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.affiliation: Inserm, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.|Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Vecht
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D018709:Statistics, Nonparametric; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Glioblastoma; Methylation; Microenvironment; Progression; Recurrence