Journal of Molecular Medicine

, Volume 83, Issue 12, pp 976–983

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

DOI: 10.1007/s00109-005-0699-4

Cite this article as:
Sihto, H., Puputti, M., Pulli, L. et al. J Mol Med (2005) 83: 976. doi:10.1007/s00109-005-0699-4

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 receptorTyrosine kinase receptorsLung neoplasmsGlioblastomaMutation

Abbreviations

EGFR

Epidermal growth factor receptor

BAC

Bronchoalveolar carcinoma

DHPLC

Denaturing high-performance liquid chromatography

FISH

Fluorescence in situ hybridization

NSCLC

Non-small cell lung cancer

PCR

Polymerase chain reaction

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