title: EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.
abstract: OBJECTIVE
  It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non-small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. PATIENTS AND METHODS We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach--direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations.
  
  
  RESULTS
  There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing.
  
  
  CONCLUSIONS
  Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.
authors.affiliation: Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy. amarchetti@unich.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Carla
authors.initials: C
authors.lastname: Martella
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Fabio
authors.initials: F
authors.lastname: Barassi
authors.forename: Simona
authors.initials: S
authors.lastname: Salvatore
authors.forename: Antonio
authors.initials: A
authors.lastname: Chella
authors.forename: Pier P
authors.initials: PP
authors.lastname: Camplese
authors.forename: Teodorico
authors.initials: T
authors.lastname: Iarussi
authors.forename: Felice
authors.initials: F
authors.lastname: Mucilli
authors.forename: Andrea
authors.initials: A
authors.lastname: Mezzetti
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: Rocco
authors.initials: R
authors.lastname: Sacco
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D066246:ErbB Receptors