title: Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer.
abstract: The threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene has been reported in progressing lesions after gefitinib treatment in non-small cell lung cancer (NSCLC) that causes sensitive tumors to become resistant to gefitinib. Alternatively, the EGFR T790M mutation might be present in small fractions of tumor cells before drug treatment, and the tumor cells harboring the T790M mutation might be enriched during the proliferation after drug treatment. We developed a mutant-enriched PCR assay to detect small fractions of cells with T790M mutation and used this technique to detect mutations in 280 NSCLCs, including gefitinib-treated 95 cases. Although the direct sequencing detected only 1 T790M mutant case, the mutant-enriched PCR (confirmed to enrich one mutant out of 1 x 10(3) wild-type alleles) detected 9 additional cases among 280 cases. As linkage to clinicopathologic factors, the T790M mutation showed no bias for sex, smoking status, or histology but was significantly more frequent in advanced tumors (9 of 111 cases) than in early-stage tumors (1 of 169 cases; P = 0.0013). Among gefitinib-treated cases, gefitinib-sensitive mutations were found in 30 cases. The T790M mutation was present in 3 of 7 no-responders with the gefitinib-sensitive mutation and was not present in 19 responders (P = 0.014). Our results indicate that the T790M mutation is sometimes present in a minor population of tumor cells during the development of NSCLC and suggest that the detection of small fractions of T790M mutant alleles may be useful for predicting gefitinib resistance of NSCLCs with sensitive EGFR mutations.
authors.affiliation: Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Inukai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Sachio
authors.initials: S
authors.lastname: Ito
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asano
authors.forename: Shuji
authors.initials: S
authors.lastname: Ichihara
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suehisa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ouchida
authors.forename: Keisuke
authors.initials: K
authors.lastname: Aoe
authors.forename: Motoi
authors.initials: M
authors.lastname: Aoe
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008715:Methionine; D009154:Mutation; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use; D013912:Threonine; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D013912:Threonine; D008715:Methionine; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib