Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1

Vandamme, Timon; Peeters, Marc; Dogan, Fadime; Pauwels, Patrick; Assche, Elvire Van; Beyens, Matthias; Mortier, Geert; Vandeweyer, Geert; Herder, Wouter W. de; Camp, Guy Van; Hofland, Leo J.; Beeck, Ken Op de

doi:10.1530/jme-14-0304

Cited by 87 publications

(91 citation statements)

References 50 publications

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“…GOT1 had partial losses on 18q encompassing the tumour suppressor SMAD4, which is believed to be haploinsufficient (Howe et al 1998, Xu et al 2000, Alberici et al 2006. BON-1 had homozygous loss of the tumour suppressor genes CDKN2A and CDKN2B, an event that has previously been reported in this cell line (Vandamme et al 2015). The QGP-1 cell line had amplifications involving three segments on chromosome 12, including the genes MDM2 and HMGA2.…”

Section: :3mentioning

confidence: 54%

“…Recently, efforts have been made to characterise PanNET-derived cell lines BON-1 and QGP-1 by exome sequencing and genome-wide copy number analysis. These studies have raised questions regarding their relevance as models due to the absence of PanNETassociated mutations (Boora et al 2015, Vandamme et al 2015. There have been no corresponding efforts to characterise NET cell lines derived from SINETs.…”

Section: Introductionmentioning

confidence: 99%

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

Hofving¹,

Arvidsson²,

Almobarak³

et al. 2018

Endocrine-Related Cancer

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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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Section: :3mentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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

Hofving¹,

Arvidsson²,

Almobarak³

et al. 2018

Endocrine-Related Cancer

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“…In addition, this cell line also has a specific molecular/metabolic background which does not reflect the heterogeneity of human tumors. Finally, the genes mutated in BON-1 and PNET are clearly different [3,13]. The heterogeneity of pre-everolimus adjuvant treatments in our cohort may also have selected a tumor clone genetically further away from the cell lines.…”

Section: Discussionmentioning

confidence: 99%

Gly388Arg FGFR4 Polymorphism Is Not Predictive of Everolimus Efficacy in Well-Differentiated Digestive Neuroendocrine Tumors

Cros

Moati²,

Raffenne

et al. 2015

Neuroendocrinology

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Introduction: Preclinical data suggest that the single nucleotide polymorphism substituting a glycine for an arginine in codon 388 of the FGFR4 transmembrane domain may increase the proliferation of xenografted neuroendocrine cell lines and decrease their sensitivity to everolimus by modulating STAT3 signaling and the mTOR pathway. Aim: To evaluate the prognostic and predictive values of this polymorphism on everolimus efficacy in patients treated for digestive neuroendocrine tumor (NET). Patients and Methods: This monocentric retrospective cohort included patients with small bowel NET (SBNET) and pancreatic NET (PNET) treated with everolimus (2006-2013). The patients were genotyped by classical sequencing, and mTOR pathway activity was assessed by immunochemistry on formalin-fixed paraffin-embedded samples (PTEN/pPTEN/pAKT/pmTOR/pS6/p4EBP1). Results: Forty-one patients (21 males, median age 57 years) with PNET (n = 28), SBNET (n = 12) or NET of unknown origin (n = 1), grade 1 (n = 8), 2 (n = 27), 3 (n = 3) or unknown grade (n = 3), were studied. At least one 388Arg allele was found in 14/23 PNET and 10/11 SBNET. Progression-free survival in the whole population and the PNET subgroup was not influenced by the presence of one or two 388Arg alleles [HR = 1.31 (0.58-2.99), p = 0.52 and HR = 1.11 (0.45-2.73), p = 0.82, respectively]. Similarly, overall survival was not influenced. Finally, mTOR pathway molecule expression was not modified by the presence of at least one 388Arg allele. Conclusion: The Gly388Arg FGFR4 polymorphism does not seem to have a prognostic value in digestive NET. In addition, it neither predicts the response to everolimus nor modifies the activation of the mTOR pathway.

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“…However hypotheses based on extrapolation of data from basic NET research needs to be thoroughly tested in a clinical setting. There is an on-going debate whether currently available NET models are representative for human NET disease, supported by the discrepancies of the genomic landscape between NETs and commonly used cell lines (163,164). Interpretation of basic science data must therefore be made with caution.…”

Section: Authors Perspectives and Future Implicationsmentioning

confidence: 99%

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Crona

Skogseid

2016

European Journal of Endocrinology

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Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

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Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1

Cited by 87 publications

References 50 publications

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

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

Gly388Arg FGFR4 Polymorphism Is Not Predictive of Everolimus Efficacy in Well-Differentiated Digestive Neuroendocrine Tumors

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

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