title: Loss of Chromosome 18 in Neuroendocrine Tumors of the Small Intestine: The Enigma Remains.
abstract: Neuroendocrine tumors of the small intestine (SI-NETs) exhibit an increasing incidence and high mortality rate. Until now, no fundamental molecular event has been linked to the tumorigenesis and progression of these tumors. Only the loss of chromosome 18 (Chr18) has been shown in up to two thirds of SI-NETs, whereby the significance of this alteration is still not understood. We therefore performed the first comprehensive study to identify Chr18-related events at the genetic, epigenetic and gene/protein expression levels.
  
  
  
  We did expression analysis of all seven putative Chr18-related tumor suppressors by quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. Next-generation exome sequencing and SNP array analysis were performed with five SI-NETs with (partial) loss of Chr18. Finally, we analyzed all microRNAs (miRNAs) located on Chr18 by qRT-PCR, comparing Chr18+/- and Chr18+/+ SI-NETs.
  
  
  
  Only DCC (deleted in colorectal cancer) revealed loss of/greatly reduced expression in 6/21 cases (29%). No relevant loss of SMAD2, SMAD4, elongin A3 and CABLES was detected. PMAIP1 and maspin were absent at the protein level. Next-generation sequencing did not reveal relevant recurrent somatic mutations on Chr18 either in an exploratory cohort of five SI-NETs, or in a validation cohort (n = 30). SNP array analysis showed no additional losses. The quantitative analysis of all 27 Chr18-related miRNAs revealed no difference in expression between Chr18+/- and Chr18+/+ SI-NETs.
  
  
  
  DCC seems to be the only Chr18-related tumor suppressor affected by the monoallelic loss of Chr18 resulting in a loss of DCC protein expression in one third of SI-NETs. No additional genetic or epigenetic alterations were present on Chr18.
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Nieser
authors.forename: Tobias
authors.initials: T
authors.lastname: Henopp
authors.forename: Joachim
authors.initials: J
authors.lastname: Brix
authors.forename: Laura
authors.initials: L
authors.lastname: Stoß
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.forename: Wael
authors.initials: W
authors.lastname: Naboulsi
authors.forename: Martin
authors.initials: M
authors.lastname: Anlauf
authors.forename: Anna M
authors.initials: AM
authors.lastname: Schlitter
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.forename: Thomas
authors.initials: T
authors.lastname: Gress
authors.forename: Roland
authors.initials: R
authors.lastname: Moll
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Anna E
authors.initials: AE
authors.lastname: Heverhagen
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaemmerer
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Jan
authors.initials: J
authors.lastname: Sperveslage
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002869:Chromosome Aberrations; D016213:Cyclins / Q000378:metabolism; D000075389:DCC Receptor; D000075065:Elongin; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C486568:CABLES1 protein, human; D002352:Carrier Proteins; D016213:Cyclins; D000075389:DCC Receptor; C501909:DCC protein, human; C000616399:ELOA3P pseudogene, human; D000075065:Elongin; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins