Molecular diagnosis of diffuse gliomas through sequencing of cell-free circulating tumour DNA from cerebrospinal fluid

Purpose: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analysed, into IDH-wildtype glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, 11.2 respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the sub-classification of diffuse gliomas. Conclusions:The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients.

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