A five-CpG signature of microRNA methylation in non-G-CIMP glioblastoma

En-Ming Kang (1) , An-An Yin (1) , Ya-Long He (1) , Wei-Jun Chen (2) , Amandine Etcheverry (3, 4, 5) , Marc Aubry (4, 6) , Jill Barnholtz-Sloan (7) , Jean Mosser (3, 4, 5) , Wei Zhang (1) , Xiang Zhang (1)

1 Xijing Hospital
2 NJU - Nanjing University
3 IGDR - Institut de Génétique et Développement de Rennes
4 SFR UMS CNRS 3480 - INSERM 018 - Biosit : biologie, santé, innovation technologique
5 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
6 Plateforme Génomique Santé Biogenouest®
7 Case Western Reserve University [Cleveland]

Aims: DNA methylation has been found to regulate microRNAs (miRNAs) expression, but the prognostic value of miRNA-related DNA methylation aberration remained largely elusive in cancers including glioblastomas (GBMs). This study aimed to investigate the clinical and biological feature of miRNA methylation in GBMs of non-gli-oma-CpG island methylator phenotype (non-G-CIMP).Methods: Prognostic miRNA methylation loci were analyzed, with TCGA and Rennes cohort as training sets, and independent datasets of GBMs and low-grade gliomas (LGGs) were obtained as validation sets. Different statistical and bioinformatic analysis and experimental validations were performed to clinically and biologically characterize the signature.Results: We identified and validated a risk score based on methylation status of five miRNA-associated CpGs which could predict survival of GBM patients in a series of training and validation sets. This signature was independent of age and O-6-methyl-guanine-DNA methyltransferase (MGMT) promoter methylation status. The risk subgroup was associated with angiogenesis and accordingly differential responses to bevacizumab-contained therapy. MiRNA target analysis and in vitro experiments further confirmed the accuracy of this signature.Conclusion: The five-CpG signature of miRNA methylation was biologically relevant and was of potential prognostic and predictive value for GBMs. It might be of help for improving individualized treatment. K E Y W O R D S angiogenesis, DNA methylation signature, glioblastoma, miRNA, prognostication

Mots clés: DNA methylation signature; angiogenesis; glioblastoma; prognostication; miRNA

Domaines: Neurobiologie; Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]

En-Ming Kang, An-An Yin, Ya-Long He, Wei-Jun Chen, Amandine Etcheverry, et al.. A five-CpG signature of microRNA methylation in non-G-CIMP glioblastoma. CNS Neuroscience and Therapeutics, 2019, 25 (9), pp.937-950. ⟨10.1111/cns.13133⟩. ⟨hal-02121050⟩