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Original Paper

Loss of Chromosome 18 in Neuroendocrine Tumors of the Small Intestine: The Enigma Remains

Nieser M.a · Henopp T.a · Brix J.a · Stoß L.a · Sitek B.b · Naboulsi W.b · Anlauf M.c · Schlitter A.M.d · Klöppel G.d · Gress T.e · Moll R.f · Bartsch D.K.g · Heverhagen A.E.g · Knoefel W.T.h · Kaemmerer D.i · Haybaeck J.j · Fend F.a · Sperveslage J.a · Sipos B.a

Author affiliations

aInstitute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, bMedizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, cInstitute of Pathology and Cytology, St. Vincenz-Krankenhaus, Limburg, dDepartment of Pathology, Technische Universität München, Munich, eDepartment of Gastroenterology and Endocrinology, University Hospital of Marburg, fInstitute of Pathology, Philipps-Universität Marburg, and gDepartment of Visceral, Thorax and Vascular Surgery, University Hospital of Marburg, Marburg, hDepartment of General, Visceral and Pediatric Surgery, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, and iDepartment of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany; jInstitute of Pathology, Medical University Graz, Graz, Austria

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Neuroendocrinology 2017;104:302-312

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: January 12, 2016
Accepted: May 15, 2016
Published online: May 25, 2016
Issue release date: March 2017

Number of Print Pages: 11
Number of Figures: 5
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

Abstract

Background/Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

© 2016 S. Karger AG, Basel


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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: January 12, 2016
Accepted: May 15, 2016
Published online: May 25, 2016
Issue release date: March 2017

Number of Print Pages: 11
Number of Figures: 5
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN


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