Loss of DAXX and ATRX Are Associated With Chromosome Instability and Reduced Survival of Patients With Pancreatic Neuroendocrine Tumors

Marinoni, Ilaria; Kurrer, Anja Schmitt; Vassella, Erik; Dettmer, Matthias S.; Rudolph, Thomas; Banz, Vanessa; Hunger, Fabio; Pasquinelli, Silvan; Speel, Ernst‐Jan M.; Perren, Aurel

doi:10.1053/j.gastro.2013.10.020

Cited by 367 publications

(382 citation statements)

References 29 publications

Supporting

Mentioning

353

Contrasting

Unclassified

Order By: Relevance

“…Patients with loss of DAXX or ATRX expression in PanNET have a poorer prognosis in surgical series (Marinoni et al 2014, Singhi et al 2017. Additionally, loss of DAXX or ATRX is associated with chromosome instability (CIN) possibly explaining the presence of chromosomal instability in a subset of more aggressive PanNET (Marinoni et al 2014, Pipinikas et al 2015, Scarpa et al 2017. DAXX/ATRX loss is found almost exclusively in sporadic PanNET >2 cm (Marinoni et al 2014) and the same is true for DAXX/ATRX mutations in MEN1 patients (de Wilde et al 2012).…”

Section: Chromatinmentioning

confidence: 99%

“…Protein loss as well as mutations in DAXX or ATRX strongly correlates with the ALT phenotype in PanNET (Heaphy et al 2011). Patients with loss of DAXX or ATRX expression in PanNET have a poorer prognosis in surgical series (Marinoni et al 2014, Singhi et al 2017. Additionally, loss of DAXX or ATRX is associated with chromosome instability (CIN) possibly explaining the presence of chromosomal instability in a subset of more aggressive PanNET (Marinoni et al 2014, Pipinikas et al 2015, Scarpa et al 2017.…”

Section: Chromatinmentioning

confidence: 99%

See 1 more Smart Citation

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

Self Cite

102

View full text Add to dashboard Cite

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.

show abstract

Section: Chromatinmentioning

confidence: 99%

Section: Chromatinmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

Self Cite

102

View full text Add to dashboard Cite

show abstract

“…Mutations in ATRX are common in various gliomas [37,38] and pancreatic neuroendocrine tumours [23,39]. The effect of ATRX mutation on prognosis is variable; several studies found an enhanced survival with ATRX mutation in some tumour types [39] but others report a worse prognosis [23,24].…”

Section: Be Howitt Et Almentioning

confidence: 99%

Targeted genomic analysis of Müllerian adenosarcoma

Howitt

Sholl

Cin

et al. 2014

The Journal of Pathology

View full text Add to dashboard Cite

Müllerian adenosarcoma (MA) is a rare mixed mesenchymal tumour of the female genital tract, composed of malignant stroma and benign-appearing epithelium. Sarcomatous overgrowth (SO) is the only established histological variable associated with higher stage and shorter survival. Specific molecular or immunohistochemistry (IHC) tools for the diagnosis of MA are lacking. Our goal was to study genomic mutations and copy number variations (CNVs) in MA to understand better its pathobiology, and develop specific diagnostic and prognostic tools. DNA was extracted from 20 samples of MA from 18 subjects (12 without SO and 6 with SO), including two in which areas of both typical MA histology and SO were independently tested. Samples were analysed using a targeted next-generation sequencing assay interrogating exonic sequences of 275 cancer genes for mutations and CNVs as well as 91 introns across 30 genes for cancer-associated rearrangements. The mean number of mutations in MA with SO (mean 9.7; range 3-14) did not differ significantly from that in MA without SO (mean 9.6; range 5-16). MA with SO had significantly higher mean numbers of gene-level CNVs (24.6) compared to MA without SO (5; p = 0.0002). The most frequent amplification involved MDM2 and CDK4 (5/18; 28%), accompanied by focal CDK4 and MDM2 and diffuse HMGA2 expression using immunohistochemistry. MYBL1 amplification was seen in 4/18 (22%), predominantly in SO. Alterations in PIK3CA/AKT/PTEN pathway members were seen in 13/18 (72%). Notably, TP53 mutations were uncommon, present in only two cases with SO. Three out of 18 (17%) had mutations in ATRX, all associated with SO. No chromosomal rearrangements were identified. We have identified a number of recurrent genomic alterations in MA, including some associated with SO. Although further investigation of these findings is needed, confirmation of one or more may lead to new mechanistic insights and novel markers for this often difficult-to-diagnose tumour.

show abstract

“…It comes as no surprise therefore that such a gene implicated in almost every aspect of tumorigenesis in various malignancies seems to have a role in NETs. It has been suggested that ATRX and DAXX mutations are not involved in the initial phase of tumorigenesis but instead represent late events in the malignant cascade [14]. The proposed pathogenic mechanism of ATRX and DAXX deficiency is the induction of the alternative lengthening of telomeres (ALT) phenotype, in pNETs among other solid tumors.…”

Section: Genetics In Gep-netsmentioning

confidence: 99%

“…ALT phenotype triggers genome rearrangements, defects in the G2/M checkpoint control, prominent micronucleation and altered doublestrand break repair mechanisms [15]. ATRX and DAXX mutated sporadic pNETs feature chromosomal instability and are associated with worse prognosis, in terms of advanced stage, metastatic disease, reduced tumorfree intervals and decreased survival [14].…”

Section: Genetics In Gep-netsmentioning

confidence: 99%

The Role of Genetics in Sporadic GEP-NETs: A Comprehensive Review of the Literature

Fotopoulos

Vathiotis

Nikou

et al. 2017

Forum of Clinical Oncology

View full text Add to dashboard Cite

Neuroendocrine tumors (NETs) are composed of a heterogeneous group of malignancies from neuroendocrine cell compartments, with roles in both the endocrine and the nervous system. The majority of NETs are gastroenteropancreatic (GEP) in origin, arising in the foregut, midgut, or hindgut. The genomic landscape of GEP-NETs has been scarcely studied in terms of genomic profiling.The following algorithm was followed using the keywords neuroendocrine, genomics, targeted therapy, personalized medicine, gastroenteropancreatic and NET. The search was performed in PubMed and ScienceDirect database. Our current knowledge of sporadic GEP-NETs genetics must be further advanced to elucidate the molecular basis and pathogenesis of the disease, improve the accuracy of diagnosis, and guide tailor-made therapies.

show abstract

Loss of DAXX and ATRX Are Associated With Chromosome Instability and Reduced Survival of Patients With Pancreatic Neuroendocrine Tumors

Cited by 367 publications

References 29 publications

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Targeted genomic analysis of Müllerian adenosarcoma

The Role of Genetics in Sporadic GEP-NETs: A Comprehensive Review of the Literature

Contact Info

Product

Resources

About