title: Membranous expression of ectodomain isoforms of the epidermal growth factor receptor predicts outcome after chemoradiotherapy of lymph node-negative cervical cancer.
abstract: OBJECTIVE
  We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.
  
  
  METHODS
  Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.
  
  
  RESULTS
  Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node-negative patients (locoregional control, P = 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.
  
  
  CONCLUSIONS
  Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer.
authors: Department of Radiation Biology, The Norwegian Radium Hospital, Oslo, Norway.
authors: Cathinka
authors: C
authors: Halle
authors: Malin
authors: M
authors: Lando
authors: Debbie Hege
authors: DH
authors: Svendsrud
authors: Trevor
authors: T
authors: Clancy
authors: Marit
authors: M
authors: Holden
authors: Kolbein
authors: K
authors: Sundfør
authors: Gunnar B
authors: GB
authors: Kristensen
authors: Ruth
authors: R
authors: Holm
authors: Heidi
authors: H
authors: Lyng
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D002462:Cell Membrane / Q000378:metabolism; D059248:Chemoradiotherapy; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*
chemical_list: D020033:Protein Isoforms; D066246:ErbB Receptors