Original Article

Journal of Molecular Medicine

, Volume 83, Issue 12, pp 976-983

First online:

Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors

  • Harri SihtoAffiliated withLaboratory of Molecular Oncology Email author 
  • , Marjut PuputtiAffiliated withLaboratory of Molecular Oncology
  • , Laura PulliAffiliated withLaboratory of Molecular Oncology
  • , Olli TynninenAffiliated withDepartment of Pathology, Helsinki University Central Hospital (HUSLAB) and University of Helsinki
  • , Walter KoskinenAffiliated withOtorhinolaryngology-Head and Neck Surgery, Helsinki University Central Hospital
  • , Leena-Maija AaltonenAffiliated withOtorhinolaryngology-Head and Neck Surgery, Helsinki University Central Hospital
  • , Minna TannerAffiliated withDepartment of Oncology, Tampere University Central Hospital
  • , Tom BöhlingAffiliated withDepartment of Pathology, Helsinki University Central Hospital (HUSLAB) and University of Helsinki
  • , Tapio VisakorpiAffiliated withInstitute of Medical Technology, University of Tampere and Tampere University Hospital
    • , Ralf BützowAffiliated withDepartment of Pathology, Helsinki University Central Hospital (HUSLAB) and University of Helsinki
    • , Aija KnuuttilaAffiliated withDepartment of Pulmonary Medicine, Helsinki University Central Hospital
    • , Nina N. NupponenAffiliated withLaboratory of Molecular Oncology
    • , Heikki JoensuuAffiliated withDepartment of Oncology, Helsinki University Central Hospital

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

Mutations that may predict response to adenosine 5′-triphosphate (ATP)-mimetic epidermal growth factor receptor (EGFR) inhibitors occur in the EGFR kinase domain in lung adenocarcinomas and bronchioloalveolar carcinomas (BACs). Data on the frequency of EGFR mutations are sparse in other human tumors. Apart from the deletion mutant EGFRvIII, little is known about the frequency of mutations that encode for the EGFR extracellular domains II and IV that participate in receptor dimerization and formation of the tethered (autoinhibited) receptor conformation. We investigated 566 human neoplasms consisting of various histological types for mutations in exons 6, 7 (encode domain II), 14, 15 (domain IV), 18, 19, and 21 (the kinase domain) using denaturing high-performance liquid chromatography (DHPLC). Approximately 4,500 EGFR exons were screened for the presence of a mutation, and samples with an abnormal finding in DHPLC were sequenced. Only one mutation was found in the extracellular domain IV (glioblastoma), and none in domain II. Eight (11%) out of the 40 lung adenocarcinomas, or 33 BACs, investigated had exon 19 or 21 mutation in the kinase domain, but no mutations were found in other tumor types. Most of the lung cancers with mutated EGFR had three to six copies of the mutated gene in fluorescence in situ hybridization. We conclude that mutations of the EGFR kinase domain and the cysteine-rich extracellular domains are infrequent in most types of human cancer apart from lung adenocarcinoma. Mutated EGFR is usually not amplified in lung cancer.

Keywords

Epidermal growth factor receptor Tyrosine kinase receptors Lung neoplasms Glioblastoma Mutation