title: EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review.
abstract: For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra-cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ∼85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients' sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape.
authors.affiliation: Dept of IHC & Mol Biology, 401 GAH, Athens, Greece; Dept of Pathology, Medical School, University of Athens, Greece. Electronic address: tsiambasecyto@yahoo.gr.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Tsiambas
authors.affiliation: Faculty of Medicine, University of Southampton, UK.
authors.forename: Alicia Y
authors.initials: AY
authors.lastname: Lefas
authors.affiliation: Dept of Breast Cancer Surgery, Blue Cross Hospital, Greece.
authors.forename: Stavros N
authors.initials: SN
authors.lastname: Georgiannos
authors.affiliation: Dept of Maxillofacial, School of Medicine, University of Ioannina, Greece.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Ragos
authors.affiliation: Dept of Pathology, Medical School, University of Athens, Greece.
authors.forename: Panagiotis P
authors.initials: PP
authors.lastname: Fotiades
authors.affiliation: 3rd Dept of Medicine, Athens School of Medicine, "Sotiria" General Hospital, Athens, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Grapsa
authors.affiliation: Dept of Thoracic Surgery, KAT Hopsital, Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stamatelopoulos
authors.affiliation: Dept of Pathology, Medical School, University of Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kavantzas
authors.affiliation: Dept of Pathology, Medical School, University of Athens, Greece.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.affiliation: 3rd Dept of Medicine, Athens School of Medicine, "Sotiria" General Hospital, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Syrigos
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: amplification; epidermal growth factor receptor (EGFR); genes; lung cancer; mutation