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The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Journal article
Authors Tobias Hofving
Yvonne Arvidsson
Bilal Almobarak
Linda Inge
R. Pfragner
Marta Persson
Göran Stenman
Erik Kristiansson
Viktor Johanson
Ola Nilsson
Published in Endocrine-Related Cancer
Volume 25
Issue 3
Pages 367-380
ISSN 1351-0088
Publication year 2018
Published at Department of Mathematical Sciences
Institute of Clinical Sciences, Department of Surgery
Institute of Biomedicine, Department of Pathology
Sahlgrenska Cancer Center
Pages 367-380
Language en
Keywords neuroendocrine tumour, GEPNET, immunophenotyping, copy number alterations, exome, nude-mice, ileal carcinoids, gene-expression, sequencing data, valproic, acid, mtor pathway, tumor-cells, establishment, cancer, landscape
Subject categories Cancer and Oncology, Endocrinology


Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

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