Prognostic stratification of adult primary glioblastoma multiforme patients based on their tumor gene amplification profiles
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María González-Tablas1, Inês Crespo2,3, Ana Luísa Vital2,3, Álvaro Otero4, Ana Belén Nieto5, Pablo Sousa4, María Carmen Patino-Alonso5, Luis Antonio Corchete6, Hermínio Tão7, Olinda Rebelo8, Marcos Barbosa7,9, Maria Rosário Almeida2, Ana Filipa Guedes2, María Celeste Lopes2,3, Pim J. French10, Alberto Orfao1,11,* and María Dolores Tabernero1,11,*
1Centre for Cancer Research (CIC IBMCC-CSIC/USAL), Department of Medicine, CIBERONC, University of Salamanca, Salamanca, Spain
2Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
3Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
4Servicio de Neurocirugía, Hospital Universitario e Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain
5Department of Statistics, University of Salamanca, Salamanca, Spain
6Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain
7Neurosurgery Service, University Hospital of Coimbra, Coimbra, Portugal
8Neuropathology Laboratory, Neurology Service, University Hospital of Coimbra, Coimbra, Portugal
9Faculty of Medicine, University of Coimbra, Coimbra, Portugal
10Department of Neurology, Erasmus MC, Rotterdam, The Netherlands
11Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain
*Both authors have equally contributed to this work and should be considered as last authors
María Dolores Tabernero, email: [email protected]
Keywords: glioblastoma; classification; subtypes; gene amplification; survival
Received: February 28, 2018 Accepted: May 14, 2018 Published: June 15, 2018
Several classification systems have been proposed to address genomic heterogeneity of glioblastoma multiforme, but they either showed limited prognostic value and/or are difficult to implement in routine diagnostics. Here we propose a prognostic stratification model for these primary tumors based on tumor gene amplification profiles, that might be easily implemented in routine diagnostics, and potentially improve the patients management. Gene amplification profiles were prospectively evaluated in 80 primary glioblastoma multiforme tumors using single-nucleotide polymorphism arrays and the results obtained validated in publicly available data from 267/347 cases. Gene amplification was detected in 45% of patients, and chromosome 7p11.2 including the EGFR gene, was the most frequently amplified chromosomal region – either alone (18%) or in combination with amplification of DNA sequences in other chromosomal regions (10% of cases). Other frequently amplified DNA sequences included regions in chromosomes 12q(10%), 4q12(7%) and 1q32.1(4%). Based on their gene amplification profiles, glioblastomas were subdivided into: i) tumors with no gene amplification (55%); ii) tumors with chromosome 7p/EGFR gene amplification (with or without amplification of other chromosomal regions) (38%); and iii) glioblastoma multiforme with a single (11%) or multiple (6%) amplified DNA sequences in chromosomal regions other than chromosome 7p. From the prognostic point of view, these amplification profiles showed a significant impact on overall survival of glioblastoma multiforme patients (p>0.001). Based on these gene amplification profiles, a risk-stratification scoring system was built for prognostic stratification of glioblastoma which might be easily implemented in routine diagnostics, and potentially contribute to improved patient management.
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