Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression

ABSTRACTRecent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. We examined whether tumour DNA methylation (DNAme) profiling combined with genomic data could identify cell of origin and reveal pathways involved in PanNET progression. We analysed genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigated ARX and PDX1 expression. Based on epigenetic similarities, PanNETs clustered in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreased in the intermediate tumours, which presented unclear differentiation. Specific transcription factor methylation and expression varied in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.

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Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression

Communications Biology ◽

10.1038/s42003-020-01479-y ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Annunziata Di Domenico ◽

Christodoulos P. Pipinikas ◽

Renaud S. Maire ◽

Konstantin Bräutigam ◽

Cedric Simillion ◽

...

Keyword(s):

Neuroendocrine Tumours ◽

Tumour Progression ◽

Cell Of Origin ◽

Β Cells ◽

Mutational Spectra ◽

Genome Wide ◽

Pancreatic Neuroendocrine Tumours ◽

Express Cell ◽

Cell Type Specific ◽

Pdx1 Expression

AbstractRecent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigate ARX and PDX1 expression. Based on epigenetic similarities, PanNETs cluster in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreases in the intermediate tumours, which present unclear differentiation. Specific transcription factor methylation and expression vary in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.

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CUX1—Transcriptional Master Regulator of Tumor Progression in Pancreatic Neuroendocrine Tumors

Cancers ◽

10.3390/cancers12071957 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1957

Author(s):

Sebastian Krug ◽

Julia Weissbach ◽

Annika Blank ◽

Aurel Perren ◽

Johannes Haybaeck ◽

...

Keyword(s):

Transcription Factor ◽

Mouse Model ◽

Neuroendocrine Tumours ◽

Tumour Progression ◽

Free Survival ◽

Treatment Naïve ◽

Pancreatic Neuroendocrine Tumours ◽

The Impact

Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; p = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.

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Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size

Gut ◽

10.1136/gutjnl-2020-322595 ◽

2021 ◽

pp. gutjnl-2020-322595 ◽

Cited By ~ 1

Author(s):

Wenzel M Hackeng ◽

Lodewijk A A Brosens ◽

Joo Young Kim ◽

Roderick O'Sullivan ◽

You-Na Sung ◽

...

Keyword(s):

Neuroendocrine Tumours ◽

Tumour Size ◽

In Situ Hybridisation ◽

Unknown Primary ◽

Fluorescence In Situ Hybridisation ◽

Death Domain ◽

Alternative Lengthening Of Telomeres ◽

Alternative Lengthening ◽

Pancreatic Neuroendocrine Tumours ◽

Pdx1 Expression

ObjectiveRecent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.DesignAn international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).ResultsATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).ConclusionsATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

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Management of multiple endocrine neoplasia type 1 (MEN1) and sporadic pancreatic neuroendocrine tumours (PNETS) in relation to the clinical guidelines: a single centre audit

Endocrine Abstracts ◽

10.1530/endoabs.44.p78 ◽

2016 ◽

Author(s):

Georgia Ntali ◽

Paul J Newey ◽

Victoria Stokes ◽

Denis Talbot ◽

Zahir Soonawalla ◽

...

Keyword(s):

Clinical Guidelines ◽

Multiple Endocrine Neoplasia ◽

Neuroendocrine Tumours ◽

Multiple Endocrine Neoplasia Type ◽

Single Centre ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Pancreatic Neuroendocrine Tumours

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Algorithm of diagnosis of pancreatic neuroendocrine tumours on fine needle aspiration specimens

10.26226/morressier.5b4709846f4cb3001095179a ◽

2018 ◽

Author(s):

Cristiana Popp ◽

Mirela Daiela Cioplea ◽

Sabina Zurac ◽

Patricia-Irina Stinga ◽

Alexandra Ioana Dragusin ◽

...

Keyword(s):

Fine Needle Aspiration ◽

Neuroendocrine Tumours ◽

Needle Aspiration ◽

Fine Needle ◽

Pancreatic Neuroendocrine Tumours

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Faculty Opinions recommendation of Laparoscopic versus open pancreas resection for pancreatic neuroendocrine tumours: a systematic review and meta-analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727348091.793531197 ◽

2017 ◽

Author(s):

Christos Dervenis ◽

Dionysia Kelgiorgi

Keyword(s):

Systematic Review ◽

Neuroendocrine Tumours ◽

Meta Analysis ◽

Pancreas Resection ◽

Pancreatic Neuroendocrine Tumours

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Imaging of Pancreatic-Neuroendocrine Tumours: An Outline of Conventional Radiological Techniques

Current Radiopharmaceuticals ◽

10.2174/1874471012666190214165845 ◽

2019 ◽

Vol 12 (2) ◽

pp. 135-155 ◽

Cited By ~ 2

Author(s):

Muhammad Affan Zamir ◽

Wasim Hakim ◽

Siraj Yusuf ◽

Robert Thomas

Keyword(s):

Neuroendocrine Tumours ◽

Treatment Options ◽

Advantages And Disadvantages ◽

Imaging Characteristics ◽

Fundamental Understanding ◽

Pancreatic Neuroendocrine Tumours ◽

Direct Management ◽

Important Disease ◽

Similar Imaging

IIntroduction: Pancreatic Neuroendocrine Tumours (p-NETs) are an important disease entity and comprise of peptide-secreting tumours often with a functional syndrome. : Accounting for a small percentage of all pancreatic tumours, they have a good overall survival rate when diagnosed early, with surgery being curative. The role of nuclear medicine in the diagnosis and treatment of these tumours is evident. However, the vast majority of patients will require extensive imaging in the form of conventional radiological techniques. It is important for clinicians to have a fundamental understanding of the p-NET appearances to aid prompt identification and to help direct management through neoplastic staging. Methods: This article will review the advantages and disadvantages of conventional radiological techniques in the context of p-NETs and highlight features that these tumours exhibit. Conclusion: Pancreatic neuroendocrine tumours are a unique collection of neoplasms that have markedly disparate clinical features but similar imaging characteristics. Most p-NETs are small and welldefined with homogenous enhancement following contrast administration, although larger and less welldifferentiated tumours can demonstrate areas of necrosis and cystic architecture with heterogeneous enhancement characteristics. : Prognosis is generally favourable for these tumours with various treatment options available. However, conventional radiological techniques will remain the foundation for the initial diagnosis and staging of these tumours, and a grasp of these modalities is extremely important for physicians.

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Peptide Receptor Radionuclide Therapy for Pancreatic Neuroendocrine Tumours

Current Radiopharmaceuticals ◽

10.2174/1874471012666190201164132 ◽

2019 ◽

Vol 12 (2) ◽

pp. 126-134 ◽

Cited By ~ 5

Author(s):

Shahad Alsadik ◽

Siraj Yusuf ◽

Adil AL-Nahhas

Keyword(s):

Side Effects ◽

Effective Treatment ◽

Radionuclide Therapy ◽

Neuroendocrine Tumours ◽

Peptide Receptor Radionuclide Therapy ◽

Progression Free Survival ◽

Treatment Modalities ◽

Effective Treatment Option ◽

Peptide Receptor ◽

Pancreatic Neuroendocrine Tumours

Background: The incidence of pancreatic Neuroendocrine Tumours (pNETs) has increased considerably in the last few decades. The characteristic features of this tumour and the development of new investigative and therapeutic methods had a great impact on its management. Objective: The aim of this review is to investigate the outcome of Peptide Receptor Radionuclide Therapy (PRRT) in the treatment of pancreatic neuroendocrine tumours. Methods: A comprehensive literature search strategy was used based on two databases (SCOPUS, and PubMed). We considered all studies published in English, evaluating the use of PRRT (177Luteciuim- DOTA-conjugated peptides and 90Yetrium- DOTA- conjugated peptides) in the treatment of pancreatic neuroendocrine tumours as a standalone entity or as a subgroup within the wider category of Gastroenteropancreatic Neuroendocrine Tumours (GEP NETs). Results: PRRT was found to be an effective treatment modality as a monotherapy or in combination with other therapies in the treatment of non-operable and metastatic pNETs where other options are limited. Complete response was reported to be between 2-6% while partial response was achieved in up to 60% of cases. Survival analysis was also impressive. Progression Free Survival (PFS) reached a mean of 34 months and Overall Survival (OS) of 53 months. PRRT also proved to improve patients’ Quality of Life (QoL). Acute and sub-acute side effects like nephrotoxicity and haematotoxicity are usually mild and reversible. Conclusion: PRRT is well tolerated and effective treatment option for non-operable and/or metastatic pNETs. Side effects are usually mild and reversible. Larger randomized controlled trails need to be done to compare PRRT with other treatment modalities and to provide more detailed guidelines regarding patient selections, the choice of PRRT, follow up and response assessment to maximum potential benefit.

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