title: Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumour leading to a dismal prognosis. Multimodality therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons for the rather poor efficacy of platinum compounds remain largely unknown.
  
  
  METHODS
  For this exploratory mRNA study, 24 FFPE tumour specimens were screened by digital gene expression analysis. Based on data from preliminary experiments and recent literature, a total of 366 mRNAs were investigated using a Custom CodeSet from NanoString. All statistical analyses were calculated with the R i386 statistical programming environment.
  
  
  RESULTS
  CDC25AandPARP1gene expression were correlated with lymph node spread,BRCA1andTP73expression levels with higher IMIG stage.NTHL1andXRCC3expression was associated with TNM stage.CHECK1as well asXRCC2expression levels were correlated with tumour progression in the overall cohort of patients.CDKN2AandMLH1gene expression influenced overall survival in this collective. In the adjuvant treated cohort only,CDKN2A,CHEK1as well asERCC1were significantly associated with overall survival. Furthermore,TP73expression was associated with progression in this subgroup.
  
  
  CONCLUSIONS
  DNA-damage response plays a crucial role in response to platin-based chemotherapeutic regimes. In particular,CHEK1,XRCC2andTP73are strongly associated with tumour progression.ERCC1, MLH1,CDKN2Aand most promisingCHEK1are prognostic markers for OS in MPM.TP73,CDKN2A,CHEK1andERCC1seem to be also predictive markers in adjuvant treated MPMs. After a prospective validation, these markers may improve clinical and pathological practice, finally leading to a patients' benefit by an enhanced clinical management.
authors.affiliation: Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;; Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Robert Fred Henry
authors.initials: RF
authors.lastname: Walter
authors.affiliation: Institute of Pathology, Division of Molecular Pathology, Charité, Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vollbrecht
authors.affiliation: Department of Pathology, Helios Klinikum Emil von Behring, Berlin Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Werner
authors.affiliation: Department of Pathology, Helios Klinikum Emil von Behring, Berlin Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mairinger
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmeller
authors.affiliation: Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Flom
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;; Institute of Pathology, Ev.-Luth. Diakonissenkrankenhaus Flensburg, Flensburg, Germany.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.affiliation: Thoracic Surgery Department, Theagenio Cancer Hospital, Thessaloniki, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Barbetakis
authors.affiliation: Thoracic Surgery Department, Theagenio Cancer Hospital, Thessaloniki, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Paliouras
authors.affiliation: Pathology Department, "Theagenio" Cancer Hospital, Thessaloniki, Greece.
authors.forename: Fotios
authors.initials: F
authors.lastname: Chatzinikolaou
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: Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Kosmas
authors.initials: K
authors.lastname: Tsakiridis
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: 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: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Daniel Christian
authors.initials: DC
authors.lastname: Christoph
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Fabian Dominik
authors.initials: FD
authors.lastname: Mairinger
keywords: DNA-damage repair; NanoString nCounter; digital gene expression analysis; platin-based chemotherapy.; pleural mesothelioma