Journal of Molecular Medicine

, Volume 83, Issue 12, pp 976–983 | Cite as

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

  • Harri Sihto
  • Marjut Puputti
  • Laura Pulli
  • Olli Tynninen
  • Walter Koskinen
  • Leena-Maija Aaltonen
  • Minna Tanner
  • Tom Böhling
  • Tapio Visakorpi
  • Ralf Bützow
  • Aija Knuuttila
  • Nina N. Nupponen
  • Heikki Joensuu
Original Article


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.


Epidermal growth factor receptor Tyrosine kinase receptors Lung neoplasms Glioblastoma Mutation 



Epidermal growth factor receptor


Bronchoalveolar carcinoma


Denaturing high-performance liquid chromatography


Fluorescence in situ hybridization


Non-small cell lung cancer


Polymerase chain reaction



Supported by grants from the Cancer Society of Finland, Foundation for the Finnish Cancer Institute, the Sigrid Juselius Foundation, and the Research Funds of Helsinki University Central Hospital.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Harri Sihto
    • 1
  • Marjut Puputti
    • 1
  • Laura Pulli
    • 1
  • Olli Tynninen
    • 2
  • Walter Koskinen
    • 3
  • Leena-Maija Aaltonen
    • 3
  • Minna Tanner
    • 5
  • Tom Böhling
    • 2
  • Tapio Visakorpi
    • 6
  • Ralf Bützow
    • 2
  • Aija Knuuttila
    • 4
  • Nina N. Nupponen
    • 1
  • Heikki Joensuu
    • 7
  1. 1.Laboratory of Molecular OncologyHelsinkiFinland
  2. 2.Department of PathologyHelsinki University Central Hospital (HUSLAB) and University of HelsinkiHelsinkiFinland
  3. 3.Otorhinolaryngology-Head and Neck SurgeryHelsinki University Central HospitalHUSFinland
  4. 4.Department of Pulmonary MedicineHelsinki University Central HospitalHUSFinland
  5. 5.Department of OncologyTampere University Central HospitalTampereFinland
  6. 6.Institute of Medical TechnologyUniversity of Tampere and Tampere University HospitalTampereFinland
  7. 7.Department of OncologyHelsinki University Central HospitalHelsinkiFinland

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