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

Artikel i vetenskaplig tidskrift
Författare Tobias Hofving
Yvonne Arvidsson
Bilal Almobarak
Linda Inge
R. Pfragner
Marta Persson
Göran Stenman
Erik Kristiansson
Viktor Johanson
Ola Nilsson
Publicerad i Endocrine-Related Cancer
Volym 25
Nummer/häfte 3
Sidor 367-380
ISSN 1351-0088
Publiceringsår 2018
Publicerad vid Institutionen för matematiska vetenskaper
Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Institutionen för biomedicin, avdelningen för patologi
Sahlgrenska Cancer Center
Sidor 367-380
Språk en
Länkar doi.org/10.1530/erc-17-0445
Ämnesord 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
Ämneskategorier Cancer och onkologi, Endokrinologi

Sammanfattning

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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