RESUMO
Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis.
Assuntos
Neoplasias Encefálicas/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/líquido cefalorraquidiano , Genômica , Neoplasias Meníngeas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/sangue , Glioblastoma/líquido cefalorraquidiano , Glioblastoma/genética , Humanos , Neoplasias Pulmonares/patologia , Meduloblastoma/sangue , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/genética , Neoplasias Meníngeas/sangue , Neoplasias Meníngeas/líquido cefalorraquidianoRESUMO
Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-ß inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-ß inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-ß pathway decreases the CD44(high)/Id1(high) GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.