title: Clinicopathologic implications of NF1 gene alterations in diffuse gliomas.
abstract: Recent studies have identified somatic alterations in the gene encoding for neurofibromin (NF1) in a subset of glioblastoma (GBM), usually associated with the mesenchymal molecular subtype. To understand the significance of NF1 genetic alterations in diffuse gliomas in general, we evaluated public databases and tested for NF1 copy number alterations in a cohort using fluorescence in situ hybridization. NF1 genetic loss (homozygous NF1 deletions or mutations with predicted functional consequences) was present in 30 (of 281) (11%) GBM and 21 (of 286) (7%) lower-grade gliomas in The Cancer Genome Atlas data. Furthermore, NF1 loss was associated with worse overall and disease-specific survival in the lower-grade glioma, but not GBM, Group in The Cancer Genome Atlas cohort. IDH1 or 2 mutations co-existed in lower-grade gliomas with NF1 loss (36%) but not in GBM. In our cohort studied by fluorescence in situ hybridization, NF1/17q (n = 2) or whole Ch17 (n = 3) losses were only identified in the GBM group (5/86 [6%]). Tumors with NF1/Ch17 loss were predominantly adult GBM (4/5); lacked EGFR amplification (0/4), strong p53 immunolabeling (1/5), or IDH1 (R132H) protein expression (0/5); but expressed the mesenchymal marker podoplanin in 4/5. NF1 genetic loss occurs in a subset of diffuse gliomas, and its significance deserves further exploration.
authors.affiliation: Department of Cellular and Tissue Biology, Faculty of Medicine, UNAM, Mexico City, Mexico 06010; Division of Neuropathology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21231.
authors.forename: M Adelita
authors.initials: MA
authors.lastname: Vizcaíno
authors.affiliation: Division of Neuropathology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21231; Rutgers Robert Wood Johnson Medical School in New Jersey, 125 Paterson Street, New Brunswick, NJ 08901.
authors.forename: Smit
authors.initials: S
authors.lastname: Shah
authors.affiliation: Division of Neuropathology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21231; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21231.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Division of Neuropathology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21231; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21231. Electronic address: frodrig4@jhmi.edu.
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D017353:Gene Deletion; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D025542:Neurofibromin 1 / Q000235:genetics*; D010641:Phenotype; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D025542:Neurofibromin 1
keywords: FISH; Glioblastoma; Glioma; NF1; Neurofibromatosis; Neurofibromin