title: Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp.
abstract: Lung cancer is one of the leading causes of the cancer death worldwide. Gefitinib is an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and has been introduced in the treatment of advanced lung cancers. The responsiveness to gefitinib has been linked to the presence of EGFR mutations. Clinical samples contain many normal cells in addition to cancer cells. A method capable of detecting EGFR mutations in a large background of wild-type EGFR genes could provide a superior clinical test. We developed a rapid and sensitive detection system for EGFR mutations named the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp that can detect EGFR mutations in the presence of 100-to 1,000-fold background of wild-type EGFR. We used this method to screen 30 non-small cell lung cancer cell lines established from Japanese patients. In addition to 11 cell lines that have mutations, we found 12 cell lines in which specific mutations are observed only in the subpopulation(s) of the cells. Genetic heterogeneity of EGFR suggests that the EGFR gene is unstable in established cancers and the heterogeneity may explain variable clinical responses of lung cancers to gefitinib.
authors.affiliation: Department of Respiratory Medicine, Saitama Medical School, Moroyama-machi, Iruma-gun, Saitama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nagai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyazawa
authors.lastname: Huqun
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Udagawa
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Kato
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Akemi
authors.initials: A
authors.lastname: Yokote
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Minoru
authors.initials: M
authors.lastname: Kanazawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000077156:Gefitinib; D005784:Gene Amplification; D018773:Genes, erbB-1 / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D020135:Peptide Nucleic Acids / Q000737:chemistry* / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods*; D011799:Quinazolines / Q000494:pharmacology; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D020135:Peptide Nucleic Acids; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib