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

ABSTRACT: 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: GSE118014 | GEO | 2018/10/01

REPOSITORIES: GEO

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

Project description:DNA CpG methylation profiling of PanNETs patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins 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.

2018-10-01 | GSE117852 | GEO

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

Project description: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.

2018-10-01 | GSE117851 | GEO

Genome-wide methylation profiling of sporadic Pancreatic Neuroendocrine Tumors

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.

2022-11-30 | E-MTAB-11962 | biostudies-arrayexpress

Genome-wide methylation profiling of sporadic Pancreatic Neuroendocrine Tumors

2022-11-30 | E-MTAB-11965 | biostudies-arrayexpress

Genome-wide methylation profiling of sporadic Pancreatic Neuroendocrine Tumors

2020-11-30 | E-MTAB-7924 | biostudies-arrayexpress

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

Project description:This study evaluate the methylation profile of 84 clinically sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent LOH and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent LOH of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs. These set of normal adjacent pancreata was compared to ICGC pancreatic neuroendocrine tumour methylation. We identified CpG sites located in promoter regions with low levels of methylation (beta value <0.3) in all normal adjacent pancreata and from those selected the most variable probes with a standard deviation >0.20 of DNA methylation levels across all tumors to identify sub-groups.

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.

2024-04-17 | GSE248606 | GEO

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

Developmental enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Project description:Most pancreatic neuroendocrine tumors (PNETs) do not produce symptoms of hormonal excess and are hence considered ‘non-functional’. Their clinical behaviors vary widely, emphasizing the need for a robust classification with prognostic power. Using enhancer maps to infer regulatory programs, we find that the large majority of non-functional PNETs fall into two major sub-types –A and B– that reflect alpha and beta endocrine cell ontogeny, respectively. A and B tumors have similar clinical presentations and histology, but express distinct lineage-specifying transcription factors, ARX or PDX1. In immunohistochemistry, 84% of 142 non-functional PNETs expressed one or the other factor, rarely both. Longitudinal data on 104 cases revealed markedly different outcomes, irrespective of MEN1 mutation status: relapse occurred almost exclusively in patients with type A tumors. These findings reveal a robust molecular stratification that provides insight into cellular origins of non-functional PNETs, accurately predicts disease course, and informs clinical decisions and future trial design.

2019-06-12 | GSE116356 | GEO

Enhancer Signatures of Neuroendocrine Tumors

Project description:<p>Most pancreatic neuroendocrine tumors (PNETs) do not produce symptoms of hormonal excess and are hence considered “non-functional”. Their clinical behaviors vary widely, emphasizing the need for a robust classification with prognostic power. Using enhancer maps to infer regulatory programs, we find that the large majority of non-functional PNETs fall into two major sub-types that reflect alpha and beta endocrine cell ontogeny, respectively. Tumors of the different subtypes have similar clinical presentations and histology, but express distinct lineage-specifying transcription factors, ARX or PDX1. Here we provide the raw ChIP-seq and RNA-seq data of the PNET cohort in this study, as well as ChIP-seq data of ileal carcinoids.</p>

| phs001910 | dbGaP

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