title: EGFR, KRAS, BRAF and ALK gene alterations in lung adenocarcinomas: patient outcome, interplay with morphology and immunophenotype.
abstract: Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphological, diagnostic and predictive biomarkers in 425 resected ADCs. Morphology was reclassified. Cytokeratin-7, thyroid transcription factor (TTF)1, napsin A, thymidylate synthase and excision repair cross-complementing rodent repair deficiency complementation group-1 expression, anaplastic lymphoma kinase rearrangements as well as epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) and v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutations were analysed. All characteristics were correlated with clinical and survival parameters. Morphological ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers, while EGFR mutations were associated with female sex, nonsmoking and lepidic as well as micropapillary growth patterns. TTF1 expression (hazard ratio (HR) for overall survival 0.61, p=0.021) and BRAF mutations (HR for disease-free survival 2.0, p=0.046) were found to be morphology- and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy, in some instances, strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers. Our data draw a comprehensive picture of the prevalence and interplay of established histological and molecular ADC characteristics. These data will help to develop time- and cost-effective diagnostic and treatment algorithms for ADC.
authors.affiliation: University Hospital Heidelberg, Heidelberg.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Heike
authors.initials: H
authors.lastname: Lindenmaier
authors.forename: Regine
authors.initials: R
authors.lastname: Brandt
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Felix J F
authors.initials: FJ
authors.lastname: Herth
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Schnabel
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Hans
authors.initials: H
authors.lastname: Hoffmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000465:Algorithms; D000077548:Anaplastic Lymphoma Kinase; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003362:Cost-Benefit Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D016130:Immunophenotyping; D053552:Keratin-7 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D012907:Smoking; D013940:Thymidylate Synthase / Q000378:metabolism; D014157:Transcription Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D053552:Keratin-7; C504003:TTF1 protein, human; D014157:Transcription Factors; D013940:Thymidylate Synthase; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016282:Aspartic Acid Endopeptidases; C498549:NAPSA protein, human