title: Copy Number Profiling of Brazilian Astrocytomas.
abstract: Copy number alterations (CNA) are one of the driving mechanisms of glioma tumorigenesis, and are currently used as important biomarkers in the routine setting. Therefore, we performed CNA profiling of 65 astrocytomas of distinct malignant grades (WHO grade I-IV) of Brazilian origin, using array-CGH and microsatellite instability analysis (MSI), and investigated their correlation with TERT and IDH1 mutational status and clinico-pathological features. Furthermore, in silico analysis using the Oncomine database was performed to validate our findings and extend the findings to gene expression level. We found that the number of genomic alterations increases in accordance with glioma grade. In glioblastomas (GBM), the most common alterations were gene amplifications (PDGFRA, KIT, KDR, EGFR, and MET) and deletions (CDKN2A and PTEN) Log-rank analysis correlated EGFR amplification and/or chr7 gain with better survival of the patients. MSI was observed in 11% of GBMs. A total of 69% of GBMs presented TERT mutation, whereas IDH1 mutation was most frequent in diffuse (85.7%) and anaplastic (100%) astrocytomas. The combination of 1p19q deletion and TERT and IDH1 mutational status separated tumor groups that showed distinct age of diagnosis and outcome. In silico validation pointed to less explored genes that may be worthy of future investigation, such as CDK2, DMRTA1, and MTAP Herein, using an extensive integrated analysis, we indicated potentially important genes, not extensively studied in gliomas, that could be further explored to assess their biological and clinical impact in astrocytomas.
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, São Paulo, 14785 002, Brazil.
authors.forename: Lucas Tadeu
authors.initials: LT
authors.lastname: Bidinotto
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Raul
authors.initials: R
authors.lastname: Torrieri
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, UK Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: Department of Pathology, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Gisele Caravina
authors.initials: GC
authors.lastname: Almeida
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4704 553, Portugal 3B's - PT Government Associate Laboratory, Braga/Guimarães, 4704 553, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Viana-Pereira
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cruvinel-Carloni
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, São Paulo, 14785 002, Brazil.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Spina
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Nathalia Cristina
authors.initials: NC
authors.lastname: Campanella
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Weder
authors.initials: W
authors.lastname: Pereira de Menezes
authors.affiliation: Department of Neurosurgery, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Carlos Afonso
authors.initials: CA
authors.lastname: Clara
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil.
authors.forename: Aline Paixão
authors.initials: AP
authors.lastname: Becker
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, UK Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, 14784 400, Brazil Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4704 553, Portugal 3B's - PT Government Associate Laboratory, Braga/Guimarães, 4704 553, Portugal ruireis.hcb@gmail.com.
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Reis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001938:Brazil; D002648:Child; D055028:Comparative Genomic Hybridization; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D009363:Neoplasm Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C000588866:KDR protein, human; C491743:MET protein, human; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040301:Vascular Endothelial Growth Factor Receptor-2; C509186:TERT protein, human; D019098:Telomerase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: IDH1; TERT; genomics; glioblastomas; gliomas