title: Folic-acid metabolism and DNA-repair phenotypes differ between neuroendocrine lung tumors and associate with aggressive subtypes, therapy resistance and outcome.
abstract: OBJECTIVE
  25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking.
  
  
  METHODS
  Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair.
  
  
  RESULTS
  Expression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS). Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001).
  
  
  CONCLUSIONS
  The assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms.
authors.affiliation: Ruhrlandklinik Essen, 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, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.|Institute of Pathology, Division of Molecular Pathology, Charité, Berlin, Germany.
authors.forename: Fabian Dominik
authors.initials: FD
authors.lastname: Mairinger
authors.affiliation: Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Werner
authors.affiliation: Institute of Pathology, Division of Molecular Pathology, Charité, Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vollbrecht
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hager
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.|Institute of Pathology, Ev.-Luth. Diakonissenkrankenhaus Flensburg, Flensburg, Germany.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.affiliation: Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Daniel Christian
authors.initials: DC
authors.lastname: Christoph
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045643:DNA Repair Enzymes / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D058975:Folate Receptor 1 / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism*; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D005492:Folic Acid; D045643:DNA Repair Enzymes
keywords: DNA repair; NanoString nCounter; folic acid metabolism; lung cancer; neuroendocrine pulmonary tumors