title: Prognostic value of rare and complex mutations in EGFR and serum levels of soluble EGFR and its ligands in non-small cell lung carcinoma patients.
abstract: BACKGROUND
  A number of complex and rare mutations in epidermal growth factor receptor (EGFR) gene have been identified and the clinical implication of serum EGFR ligands has also been reported. However, the prognostic significance of these mutations and also the serum EGFR and its ligands in Non-Small Cell Lung Carcinoma (NSCLC) has remained a challenging issue. This study is aimed at finding the prognostic importance of EGFR rare mutations and serum EGFR, amphiregulin (AR), and TGF-α (Transforming Growth Factor-alpha) in NSCLC.
  
  
  METHODS
  NSCLC patients (n=98) with mean age of 59±10.5 were enrolled (M/F: 75/23). DNA was extracted from formalin fixed paraffin embedded tissues. Exons 19 and 21 were amplified using polymerase chain reaction followed by direct sequencing for identification of mutations. Serum EGFR, AR, and TGF-α were measured by ELISA.
  
  
  RESULTS
  EGFR mutation rate in patients was 37% (exon 19 deletions: 72.2%, exon 21 substitutions: 27.8%). The E872K in exon 21 mutation-positive cases was the most frequent rare mutation detected (90%; 9/10 samples). A significant relationship was found between EGFR exon 21mutations and serum EGFR and TGF-α (P<0.05). Increased serum AR (>3pg/ml) and TGF-α (>10.5pg/ml) were associated with shorter overall survival (P<0.05).
  
  
  CONCLUSIONS
  The data clearly show that elevation of serum TGF-α and AR are associated with poor prognosis of NSCLC. In addition to the close relationship between EGFR mutations and serum EGFR, serum TGF-α changes was associated with the gene mutations. These findings could be implicated in clinical decision making related to EGFR-TKIs.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Seyyed Mortaza
authors.initials: SM
authors.lastname: Haghgoo
authors.affiliation: Department of Oncology, Chronic Respiratory Diseases Research Center and National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Adnan
authors.initials: A
authors.lastname: Khosravi
authors.affiliation: Department of Immunology, Chronic Respiratory Diseases Research Center and National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Mortaz
authors.affiliation: Department of Pathology, Chronic Respiratory Diseases Research Center and National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mihan
authors.initials: M
authors.lastname: Pourabdollah-Toutkaboni
authors.affiliation: Department of Oncology, Chronic Respiratory Diseases Research Center and National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Seifi
authors.affiliation: Safety Promotion and Injury Prevention Research Center, Department of Epidemiology, School of Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Siamak
authors.initials: S
authors.lastname: Sabour
authors.affiliation: Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address: allameha@modares.ac.ir.
authors.forename: Abdolamir
authors.initials: A
authors.lastname: Allameh
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000235:genetics / Q000556:secondary*; D000328:Adult; D066258:Amphiregulin / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000235:genetics / Q000556:secondary*; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000097:blood / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008024:Ligands; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009367:Neoplasm Staging; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D014408:Biomarkers, Tumor; D008024:Ligands; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Epidermal growth factor receptor; Ligands; Mutation; Non-small cell lung carcinoma; Prognosis