title: Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors.
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.
authors.affiliation: Laboratory of Molecular Oncology, Room B426B, 4th floor, Biomedicum, Haartmaninkatu 8, P.O. Box 700, 00029 Helsinki, Finland. harri.sihto@helsinki.fi
authors.forename: Harri
authors.initials: H
authors.lastname: Sihto
authors.forename: Marjut
authors.initials: M
authors.lastname: Puputti
authors.forename: Laura
authors.initials: L
authors.lastname: Pulli
authors.forename: Olli
authors.initials: O
authors.lastname: Tynninen
authors.forename: Walter
authors.initials: W
authors.lastname: Koskinen
authors.forename: Leena-Maija
authors.initials: LM
authors.lastname: Aaltonen
authors.forename: Minna
authors.initials: M
authors.lastname: Tanner
authors.forename: Tom
authors.initials: T
authors.lastname: Böhling
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Aija
authors.initials: A
authors.lastname: Knuuttila
authors.forename: Nina N
authors.initials: NN
authors.lastname: Nupponen
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
mesh_terms: D000595:Amino Acid Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases