Alexis B Cortot1, Mohamad Younes2, Ghislaine Martel-Planche3, Benoit Guibert4, Sylvie Isaac5, Pierre-Jean Souquet4, Frédéric Commo6, Philippe Girard7, Pierre Fouret8, Elisabeth Brambilla9, Pierre Hainaut10, Jean-Charles Soria6. 1. 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. 2. 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. 3. International Agency for Research on Cancer, Lyon, France. 4. Department of Thoracic Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France. 5. Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France. 6. Department of Translational Research, Institut Gustave Roussy, Villejuif, France; INSERM Unit 981, University Paris-South, France. 7. Thorax Department, Institut Mutualiste Montsouris, Paris, France. 8. Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; Department of Pathology, Institut Gustave Roussy, Villejuif, France. 9. Institut Albert Bonniot, INSERM U823 and Department of Pathology, Hôpital Albert Michallon, Grenoble, France. 10. International Agency for Research on Cancer, Lyon, France; International Prevention Research Institute, Lyon, France.
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. PATIENTS AND 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. CONCLUSION: 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.
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. PATIENTS AND 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. CONCLUSION: 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: Frances A Shepherd; Benjamin Lacas; Gwénaël Le Teuff; Pierre Hainaut; Pasi A Jänne; Jean-Pierre Pignon; Thierry Le Chevalier; Lesley Seymour; Jean-Yves Douillard; Stephen Graziano; Elizabeth Brambilla; Robert Pirker; Martin Filipits; Robert Kratzke; Jean-Charles Soria; Ming-Sound Tsao Journal: J Clin Oncol Date: 2017-04-28 Impact factor: 44.544
Authors: Charu Aggarwal; Christiana W Davis; Rosemarie Mick; Jeffrey C Thompson; Saman Ahmed; Seth Jeffries; Stephen Bagley; Peter Gabriel; Tracey L Evans; Joshua M Bauml; Christine Ciunci; Evan Alley; Jennifer J D Morrissette; Roger B Cohen; Erica L Carpenter; Corey J Langer Journal: JCO Precis Oncol Date: 2018-08-31
Authors: João Paulo Portela Catani; Ruan F V Medrano; Aline Hunger; Paulo Del Valle; Sandy Adjemian; Daniela Bertolini Zanatta; Guido Kroemer; Eugenia Costanzi-Strauss; Bryan E Strauss Journal: Transl Oncol Date: 2016-12 Impact factor: 4.243