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Gene expression profile of Human non-functional Pancreatic neuroendocrine tumors (PanNETs)

ABSTRACT: Gene expression profiling of PanNETs patients samples were performed to understand genotype to phenotype correlations, novel molecular subtypes and cell of origin The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117851 | GEO | 2018/10/01

REPOSITORIES: GEO

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Transcriptome of human non-functional pancreatic neuroendocrine tumors (PanNETs)

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Methylation Heterogeneity within Human non-functional Pancreatic neuroendocrine tumors (PanNETs)

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Project description:Pancreatic neuroendocrine tumors (PanNETs) account for 1-3% of all neoplasms of the pancreas. Epigenetic changes seem to be the main drivers of PanNET tumorigenesis. Indeed, the most frequent mutated genes in PanNETs are DAXX (Death domain associated protein 6), ATRX (Transcriptional Regulator ATRX) and MEN1 (menin 1), which are all involved in epigenetic regulation. The objective of the project is to study the epigenetic changes undergoing in PanNETs. Specifically, we aimed at investigating whether do exist biologically important epigenetic differences in PanNET, useful for a clinically relevant classification.

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DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

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2021-02-16 | GSE149395 | GEO

Combined deletion of MEN1, ATRX and PTEN triggers pancreatic neuroendocrine tumorigenesis in mice

Project description:Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, ATRX, and PTEN, tumor suppressors commonly mutated in human PanNETs, triggers pancreatic neuroendocrine tumorigenesis in mice. Histopathological evaluation and gene expression analyses of the developed tumors confirm the presence of PanNET hallmarks and significant overlap in gene expression patterns found in human disease. Thus, we postulate that the presented novel genetically defined neuroendocrine-specific tumor mouse is the first clinically relevant immunocompetent in vivo PanNET model.

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Tumor suppressor functions of DAXX through histone H3.3 deposition pathway in pancreatic neuroendocrine tumor

Project description:Purpose: Pancreatic neuroendocrine tumors (PanNETs) have considerable malignant potential. Frequent somatic mutations and loss of DAXX protein expression have been frequently found in PanNETs. DAXX is known as a transcriptional repressor, however, molecular functions underlying loss of DAXX remain unclear in PanNETs. Experimental Design: We evaluated DAXX-knockdown (KD) and -knockout (KO) PanNET cells were analyzed for in vitro and vivo. The target genes were screened by microarray and chromatin immunoprecipitation (ChIP) assays for DAXX, histone H3.3 and H3K9me3 complex. Results: Microarray and ChIP analyses of DAXX-KD/KO identified 13 genes as the direct targets of DAXX transcriptional repressor. Among them, 5 genes were suppressed by DAXX/H3.3/H3K9me3 pathway. DAXX-KD/KO increased sphere forming activity, but it was suppressed by knockdown of the target gene. In xenograft models, tumorigenicity was significantly increased in DAXX-KO cells with high expression of the target. Clinically, higher recurrence was recognized in PanNETs with low expression of DAXX and high expression of the target than others. Conclusions: DAXX plays as a tumor suppressor and DAXX/H3.3 complex suppresses target genes by promoting H3K9me3 in PanNETs. DAXX and its target molecule might be effective biomarkers and therapeutic candidates.

2018-06-28 | GSE93050 | GEO

Transcriptome of human non-functional pancreatic neuroendocrine tumors (PanNETs)

Project description:Transcriptome of human non-functional pancreatic neuroendocrine tumors (PanNETs)

| PRJNA484008 | ENA

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.

Project description:Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bitransgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in b-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. The utility of this model is enhanced by ability to form tumor-derived allografts. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

2021-06-10 | GSE176448 | GEO

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