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

Francisco Martínez-Ricarte, Regina Mayor, Elena Martínez-Sáez, Carlota Rubio-Pérez, Estela Pineda, Esteban Cordero, Marta Cicuéndez, Maria A. Poca, Nuria López-Bigas, Santiago Ramon y Cajal, María Vieito, Joan Carles, Josep Tabernero, Ana Vivancos, Soledad Gallego, Francesc Graus, Juan Sahuquillo, Joan Seoane

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28 Citations (Scopus)

Abstract

2018 American Association for Cancer Research. Purpose: Diffuse gliomas are the most common primary tumor 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 tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors. 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 analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification 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.
Original languageEnglish
Pages (from-to)2812-2819
JournalClinical Cancer Research
Volume24
Issue number12
DOIs
Publication statusPublished - 15 Jun 2018

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    Martínez-Ricarte, F., Mayor, R., Martínez-Sáez, E., Rubio-Pérez, C., Pineda, E., Cordero, E., Cicuéndez, M., Poca, M. A., López-Bigas, N., y Cajal, S. R., Vieito, M., Carles, J., Tabernero, J., Vivancos, A., Gallego, S., Graus, F., Sahuquillo, J., & Seoane, J. (2018). Molecular diagnosis of diffuse gliomas through sequencing of cell-free circulating tumor DNA from cerebrospinal fluid. Clinical Cancer Research, 24(12), 2812-2819. https://doi.org/10.1158/1078-0432.CCR-17-3800