title: Mutation of TP53 and alteration of p14(arf) expression in EGFR- and KRAS-mutated lung adenocarcinomas.
abstract: BACKGROUND
  In lung adenocarcinoma, inactivation of the tumor suppressor p53 may abrogate a safeguard mechanism preventing the development of tumors with activating mutations in EGFR or KRAS. To assess this hypothesis, we analyzed TP53 mutations and downregulation of p14(arf), a negative regulator of p53 activated by oncogenic signals, in a retrospective series of 96 patients with primary adenocarcinoma of the lung.
  
  
  METHODS
  Mutations in TP53 (exons 4-9), KRAS (exon 1), and EGFR (exons 18-21) were identified by direct sequencing of DNA from formalin-fixed, paraffin-embedded resected tumors. Expression of p14(arf) was semiquantitatively evaluated by immunohistochemical analysis.
  
  
  RESULTS
  TP53, KRAS, and EGFR mutations were detected in 42 of 93 (45.2%), 15 of 95 (15.8%), and 31 of 90 (34.4%) cases, respectively. Low p14(arf) expression was observed in 19 of 91 cases (20.9%). Disruption of the p53/p14(arf) pathway (defined as TP53 mutation or decreased p14(arf) expression, or both) was observed in 18 of 31 EGFR-mutated (58.1%) tumors and in 9 of 13 KRAS-mutated (69.2%) tumors.
  
  
  CONCLUSIONS
  Inactivation of the p53/p14(arf) pathway is common but not systematic in EGFR- or KRAS-mutated lung adenocarcinomas. Our work highlights the need to better investigate the association between EGFR and KRAS mutations and alterations in tumor suppressor pathways.
authors.affiliation: International Agency for Research on Cancer, Lyon, France; Department of Thoracic Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; Thoracic Oncology Department, Lille University Hospital, Université Lille Nord de France, Lille, France. Electronic address: alexis.cortot@chru-lille.fr.
authors.forename: Alexis B
authors.initials: AB
authors.lastname: Cortot
authors.affiliation: International Agency for Research on Cancer, Lyon, France; Clinical Research Unit and Department of Pharmacology, Saint-Antoine University of Medicine, University Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Younes
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Martel-Planche
authors.affiliation: Department of Thoracic Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Guibert
authors.affiliation: Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Isaac
authors.affiliation: Department of Thoracic Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Souquet
authors.affiliation: Department of Translational Research, Institut Gustave Roussy, Villejuif, France; INSERM Unit 981, University Paris-South, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.affiliation: Thorax Department, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Girard
authors.affiliation: Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; Department of Pathology, Institut Gustave Roussy, Villejuif, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
authors.affiliation: Institut Albert Bonniot, INSERM U823 and Department of Pathology, Hôpital Albert Michallon, Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: International Agency for Research on Cancer, Lyon, France; International Prevention Research Institute, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.affiliation: Department of Translational Research, Institut Gustave Roussy, Villejuif, France; INSERM Unit 981, University Paris-South, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: EGFR; KRAS; Lung adenocarcinoma; p14(arf); p53