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

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322595 ◽  
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.

Tumour Size is not a Reliable Criterion for Resection of Patients with Non-Secreting Pancreatic Neuroendocrine Tumours: Results of an International, Multi-Centre, Operative Cohort

2017 ◽  
Vol 152 (5) ◽  
pp. S1234-S1235
Author(s):  
Logan Mills ◽  
Panagiotis Drymousis ◽  
Yogesh Vashist ◽  
Christoph Burdelski ◽  
Andreas Prachalias ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Tumour Size ◽  
Reliable Criterion ◽  
Pancreatic Neuroendocrine Tumours

scholarly journals Serotonin-Secreting Neuroendocrine Tumours of the Pancreas

2020 ◽  
Vol 9 (5) ◽  
pp. 1363
Author(s):  
Anna Caterina Milanetto ◽  
Matteo Fassan ◽  
Alina David ◽  
Claudio Pasquali
Keyword(s):  
Liver Metastases ◽  
Carcinoid Syndrome ◽  
Neuroendocrine Tumours ◽  
Tumour Size ◽  
Somatostatin Analogues ◽  
High Serum ◽  
Resective Surgery ◽  
Alive With Disease ◽  
Pancreatic Neuroendocrine Tumours ◽  
Well Differentiated

Background: Serotonin-secreting pancreatic neuroendocrine tumours (5-HT-secreting pNETs) are very rare, and characterised by high urinary 5-hydroxyindole-acetic acid (5-HIAA) levels (or high serum 5-HT levels). Methods: Patients with 5-HT-secreting pancreatic neoplasms observed in our unit (1986–2015) were included. Diagnosis was based on urinary 5-HIAA or serum 5-HT levels. Results: Seven patients were enrolled (4 M/3 F), with a median age of 64 (range 38–69) years. Two patients had a carcinoid syndrome. Serum 5-HT was elevated in four patients. Urinary 5-HIAA levels were positive in six patients. The median tumour size was 4.0 (range 2.5–10) cm. All patients showed liver metastases at diagnosis. None underwent resective surgery; lymph node/liver biopsies were taken. Six lesions were well-differentiated tumours and one a poorly differentiated carcinoma (Ki67 range 3.4–70%). All but one patient received chemotherapy. Four patients received somatostatin analogues; three patients underwent ablation of liver metastases. One patient is alive with disease 117 months after observation. All the others died from disease progression after a follow-up within 158 months. Conclusions: Primary 5-HT-secreting pNETs are mostly metastatic to the liver; patients are not amenable to resective surgery. Despite high 5-HIAA urinary levels, few patients present with carcinoid syndrome. A five-year survival rate of 42.9% may be achieved with multimodal treatment.

TRKA expression and NTRK1 gene copy number across solid tumours

2018 ◽  
Vol 71 (10) ◽  
pp. 926-931 ◽  
Author(s):  
Gianluca Mauri ◽  
Emanuele Valtorta ◽  
Giulio Cerea ◽  
Alessio Amatu ◽  
Michele Schirru ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
In Situ Hybridisation ◽  
Gene Copy Number ◽  
Solid Tumours ◽  
Gene Copy ◽  
Unknown Primary ◽  
Gene Rearrangements ◽  
Fluorescence In Situ Hybridisation ◽  
Formalin Fixed Paraffin Embedded

AimsNeurotrophic Tropomyosin Kinase Receptor 1 (NTRK1) gene encodes for the protein Tropomyosin-related kinase A (TRKA). Deregulated activity of TRKA has been shown to have oncogenic potential. We present here the results of an immunohistochemical (IHC) observational cohort study of TRKA expression together with gene copy number (GCN) assessment in various solid tumours.MethodsFormalin-fixed, paraffin-embedded consecutive samples of different tumour types were tested for TRKA expression. Samples showing TRKA IHC staining in at least 10% of cells were analysed by fluorescence in situ hybridisation to assess NTRK1 gene rearrangements and/or individual GCN gain. All patients underwent this molecular assessment within the phase I ALKA-001 clinical trial.Results1043 samples were tested and annotation for histology was available in 1023. Most of the samples were colorectal adenocarcinoma (CRC) (n=550, 52.7%) and lung adenocarcinoma (n=312, 29.9%). 24 samples (2.3%) were biliary tract carcinoma (BTC). Overall, 17 (1.6%) samples were characterised by TRKA IHC expression (four weak, eight moderate, five strong): 9/17 lung adenocarcinoma, 3/17 CRC, 3/17 BTC, 1/17 thyroid cancer and 1/17 cancer of unknown primary. Of these, 1/17 with strong TRKA IHC staining displayed NTRK1 gene rearrangement and 15/17 NTRK1 GCN gain by FISH. No correlation was found between intensity of TRKA IHC staining and number of copies of NTRK1.ConclusionsTRKA expression can be found in 1.6% of solid tumours and can be paralleled by NTRK1 gene rearrangements or mostly GCN gain. The prognostic and translational therapeutic impact of the latter remains to be established.

scholarly journals Impact of tumour size on metastasis and survival in patients with pancreatic neuroendocrine tumours (PNETs): A population based study

2019 ◽  
Vol 10 (25) ◽  
pp. 6349-6357
Author(s):  
Yangyang Liu ◽  
Shufang Ye ◽  
Yabi Zhu ◽  
Xingkang He ◽  
Jie Pan ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Tumour Size ◽  
Population Based ◽  
Population Based Study ◽  
Pancreatic Neuroendocrine Tumours

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

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.

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

2020 ◽  
Author(s):  
Annunziata Di Domenico ◽  
Christodoulos P. Pipinikas ◽  
Renaud Sylvain 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. 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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