title: Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors.
abstract: Background: Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large-/small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed.Material and methods: 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology.Results: A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular,EGFRexpression was observed in the investigated tumors in a noteworthy manner. Additionally,MDM2was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor,CDKN2A, was nearly absent in all low-grade tumors.TP53showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids.Conclusion: Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors.
authors.affiliation: Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen;; Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Robert Fred Henry
authors.initials: RF
authors.lastname: Walter
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vollbrecht
authors.affiliation: Department of Oncology, University Hospital Essen, University of Duisburg-Essen.
authors.forename: Daniel
authors.initials: D
authors.lastname: Christoph
authors.affiliation: Institute of Pathology, Helios Klinikum Emil von Behring, Berlin.
authors.forename: Robert
authors.initials: R
authors.lastname: Werner
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmeller
authors.affiliation: Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen.
authors.forename: Elena
authors.initials: E
authors.lastname: Flom
authors.affiliation: Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Trakada
authors.affiliation: 2nd Department of Pulmonary Medicine, "Sotiria" Hospital of Chest Diseases, Athens, Greece.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Rapti
authors.affiliation: Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Adamidis
authors.affiliation: Medical Clinic I,''Fuerth'' Hospital, University of Erlangen, Fuerth, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hohenforst-Schmidt
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Jens
authors.initials: J
authors.lastname: Kollmeier
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mairinger
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.affiliation: Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Paul
authors.initials: P
authors.lastname: Zarogoulidis
authors.affiliation: Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Porpodis
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin, Berlin.
authors.forename: Fabian Dominik
authors.initials: FD
authors.lastname: Mairinger
keywords: NanoString; biomarkers; lung cancer.; next-generation sequencing; personalized therapy