title: Genomic landscape of pancreatic neuroendocrine tumors.
abstract: OBJECTIVE
  To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs).
  
  
  METHODS
  A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed.
  
  
  RESULTS
  Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis.
  
  
  CONCLUSIONS
  This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET.
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Gebauer
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt-Werthern
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Feller
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Keck
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Nehara
authors.initials: N
authors.lastname: Begum
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Rades
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Brabant
authors.affiliation: Niklas Gebauer, Christian Schmidt-Werthern, Veronica Bernard, Alfred C Feller, Christoph Thorns, Department of Pathology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thorns
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D023281:Genomics / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries
chemical_list: D014408:Biomarkers, Tumor
keywords: Array comparative genomic hybridization; Chromosomal aberrations; Copy number alterations; Pancreatic neuroendocrine tumors; Prognosis