Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

The homeodomain transcription factor NKX2.2 is necessary for neuroendocrine (NE) differentiation in the central nervous system and pancreas. NE tumors derived from the gut are defined by their NE phenotype, which is used for diagnosis and contributes to tumorigenicity. We hypothesized that NKX2.2 is important for NE differentiation in normal and neoplastic gut. NKX2.2 and NE marker expression was investigated in the small intestine of embryonic and adult mice using immunofluorescence (IF). To determine the role of NKX2.2 in NE differentiation of the intestine, the phenotype of Nkx2.2 (K/K) mice was examined by IF and real-time (RT)-PCR. NKX2.2 and NE marker expression in human NE tumors of the gut and normal tissues were evaluated by immunohistochemistry and qRT-PCR. NKX2.2 expression was detected in the intervillus/crypt regions of embryonic and adult mouse intestine. Co-expression of Nkx2.2 with neurogenin3 (NEUROG3) and hormones was observed in the adult intestinal crypt compartment, suggesting NKX2.2 functions in NEUROG3-positive endocrine progenitors and newly differentiated endocrine cells. In the intestine of Nkx2.2 (K/K) mice, we found a dramatic reduction in the number of cells producing numerous hormones, such as serotonin, gastrin, cholecystokinin, somatostatin, glucagon-like peptide 1 (GLP-1), and secretin, but an increase in cells producing ghrelin. NKX2.2 was expressed in most (24 of 29) human NE tumors derived from diverse primary sites. We conclude NKX2.2 functions in immature endocrine cells to control NE differentiation in normal intestine and is expressed in most NE tumors of the gut, and is therefore a novel target of diagnosis for patients with gastrointestinal NE tumors.

Section: Discussionsupporting

confidence: 92%

Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors

Wang

Gallego-Arteche²,

Iezza³

et al. 2009

“…Relevant genes at 18q21.1 include SMAD2 and SMAD4, but to date, sequencing of these genes has not revealed any mutations (Lollgen et al 2001, Kulke et al 2008. Other common losses in SI-NET occur on chromosomes 11q, 16, 9, 13 and 3p (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011. Different putative candidate tumour suppressor genes have been identified in these regions, like p16/CDKN2A on 9p, RYBP on 3p, SDHD, CASP1, 4 and 5 on 11q and CDH1 on 16q (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011.…”

Section: Small Intestinal Netmentioning

confidence: 99%

“…Other common losses in SI-NET occur on chromosomes 11q, 16, 9, 13 and 3p (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011. Different putative candidate tumour suppressor genes have been identified in these regions, like p16/CDKN2A on 9p, RYBP on 3p, SDHD, CASP1, 4 and 5 on 11q and CDH1 on 16q (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011. Several independent studies showed recurrent gains of whole chromosomes, the most common ones are on chromosomes 4, 5, 7, 14 and 20 (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011).…”

Section: Small Intestinal Netmentioning

confidence: 99%

“…Different putative candidate tumour suppressor genes have been identified in these regions, like p16/CDKN2A on 9p, RYBP on 3p, SDHD, CASP1, 4 and 5 on 11q and CDH1 on 16q (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011. Several independent studies showed recurrent gains of whole chromosomes, the most common ones are on chromosomes 4, 5, 7, 14 and 20 (Kim et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011). Andersson and coworkers demonstrated a strong correlation between gain of chromosome 14 and poor survival (Andersson et al 2009).…”

Section: Small Intestinal Netmentioning

confidence: 99%

See 1 more Smart Citation

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

102

Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

“…The most common aberration is loss on chromosome 18, which have been seen in 43-100% (Kytola et al 2001, Löllgen et al 2001, Tonnies et al 2001, Stancu et al 2003, Wang et al 2005, Kim do et al 2008, Kulke et al 2008, Andersson et al 2009, Cunningham et al 2011, Walsh et al 2011, supporting the presence of a crucial tumor suppressor gene. Mutational analyses of several putative tumor suppressor genes located at 18q21-18q22 revealed no alterations (Löllgen et al 2001, Kulke et al 2008, Cunningham et al 2011.…”

Section: Introductionmentioning

confidence: 99%

TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

Edfeldt

Ahmad

Åkerström

et al. 2013

Small intestinal neuroendocrine tumors (SI-NETs), formerly known as midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. A large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one gene copy of TCEB3C. The DNA hypomethylating agent 5-aza-2 0 -deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease in clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.