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Endocr Relat Cancer. 2018 Mar;25(3):367-380. doi: 10.1530/ERC-17-0445.

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

Author information

1
Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden tobias.hofving@gu.se.
2
Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
3
Institute of Pathophysiology and ImmunologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria.
4
Department of Mathematical SciencesChalmers University of Technology, Gothenburg, Sweden.
5
Department of SurgeryInstitute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Abstract

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.

KEYWORDS:

GEPNET; cell lines; copy number alterations; exome sequencing; immunophenotyping; inhibitor screening; neuroendocrine tumour; trametinib; vorinostat

PMID:
29444910
PMCID:
PMC5827037
DOI:
10.1530/ERC-17-0445
[Indexed for MEDLINE]
Free PMC Article

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