title: Adult diffuse gliomas produce mRNA transcripts encoding EGFR isoforms             lacking a tyrosine kinase domain.
abstract: The epidermal growth factor receptor (EGFR) gene encodes four alternatively spliced mRNA, variants 1, 2, 3 and 4, respectively, encoding the whole isoform a (EGFR) and truncated isoforms b, c and d, all of which lack the receptor's intracellular domain. In addition, a mutant EGFRvIII differs from isoform a in a truncated extracellular domain. The expression pattern of these isoforms is unknown in adult diffuse gliomas. Thus, we investigated in 47 cases: i) EGFR protein expression by immunohistochemistry using an extracellular domain-recognizing antibody (Ext-Ab) and an intracellular domain specific one (Int-Ab), ii) mRNA expression of EGFRv1, -v2, -v3, -v4 and -vIII by RT-PCR and iii) EGFR amplification by fluorescent in situ hybridization. The relation of these data with histological criteria and patient outcome was studied. The immunostaining was stronger with the Ext-Ab than with the Int-Ab. EGFRv1, -v2, -v3 and -v4 mRNA expression were highly correlated. They were expressed in all tumors, with highest levels in glioblastomas. EGFRv1 strong levels and the presence of vIII mRNAs were more closely associated with Int-Ab staining. EGFR gene amplification concerned only glioblastomas and was associated with the presence of EGFRvIII and high levels of EGFRv2, -v3 and -v4 transcripts. A pejorative outcome was associated with: histology (glioblastomas), EGFR amplification, strong Int-Ab labeling and high levels of variant mRNAs. Our results indicated that the full-length EGFR and mutant EGFRvIII are not the sole EGFR isoform expressed in diffuse gliomas. This could explain discordant immunohistochemical results reported in the literature and may have therapeutic implications.
authors.affiliation: Department of Pathology, Dupuytren University Hospital, 2 Avenue                     Martin Luther King, F-87042 Limoges, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Guillaudeau
authors.forename: Karine
authors.initials: K
authors.lastname: Durand
authors.forename: Hélène
authors.initials: H
authors.lastname: Rabinovitch-Chable
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pommepuy
authors.forename: Laura
authors.initials: L
authors.lastname: Mesturoux
authors.forename: Sandrine
authors.initials: S
authors.lastname: Robert
authors.forename: Alain
authors.initials: A
authors.lastname: Chaunavel
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Moreau
authors.forename: François
authors.initials: F
authors.lastname: Labrousse
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D015996:Survival Rate
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors