RESUMEN
IDH1-mutated gliomas are slow-growing brain tumours which progress into high-grade gliomas. The early molecular events causing this progression are ill-defined. Previous studies revealed that 20% of these tumours already have transformation foci. These foci offer opportunities to better understand malignant progression. We used immunohistochemistry and high throughput RNA profiling to characterize foci cells. These have higher pSTAT3 staining revealing activation of JAK/STAT signaling. They downregulate RNAs involved in Wnt signaling (DAAM2, SFRP2), EGFR signaling (MLC1), cytoskeleton and cell-cell communication (EZR, GJA1). In addition, foci cells show reduced levels of RNA coding for Ethanolamine-Phosphate Phospho-Lyase (ETNPPL/AGXT2L1), a lipid metabolism enzyme. ETNPPL is involved in the catabolism of phosphoethanolamine implicated in membrane synthesis. We detected ETNPPL protein in glioma cells as well as in astrocytes in the human brain. Its nuclear localization suggests additional roles for this enzyme. ETNPPL expression is inversely correlated to glioma grade and we found no ETNPPL protein in glioblastomas. Overexpression of ETNPPL reduces the growth of glioma stem cells indicating that this enzyme opposes gliomagenesis. Collectively, these results suggest that a combined alteration in membrane lipid metabolism and STAT3 pathway promotes IDH1-mutated glioma malignant progression.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Liasas de Carbono-Oxígeno/genética , Glioma/genética , Glioma/metabolismo , Isocitrato Deshidrogenasa/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Regulación hacia Abajo , Perfilación de la Expresión Génica , Glioma/patología , Humanos , Inmunohistoquímica , Metabolismo de los Lípidos , Mutación , Fosforilación , Transducción de SeñalRESUMEN
BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.
