Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours

Pipinikas, Christodoulos P.; Dibra, Harpreet; Karpathakis, Anna; Feber, Andrew; Novelli, Marco; Oukrif, Dahmane; Fusai, Guiseppe; Valente, Umberto; Caplin, Martyn; Meyer, Tim; Teschendorff, Andrew E.; Bell, Christopher G.; Morris, Tiffany; Salomoni, Paolo; Luong, TuVinh; Davidson, Brian; Beck, Stephan; Thirlwell, Christina

doi:10.1530/erc-15-0108

Cited by 57 publications

(55 citation statements)

References 9 publications

(17 reference statements)

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“…Other mechanisms regulating gene expression on epigenetic levels could partially fill this gap. Intriguingly, despite the heterogeneity in gene expression, DAXX and ATRX mutations occur mainly in G2 tumours with poor prognosis, pointing out the relevance of these genes in stratifying patients and driving tumour evolution, accompanied by vast changes of DNA methylation (Pipinikas et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Chromosomal instability is a main driver of NET tumorigenesis, which is highly associated with DNA methylation changes both in SI-NET and PanNET (Marinoni et al 2014, Pipinikas et al 2015, Karpathakis et al 2016, Marinoni et al 2017). In such a context, mutations in gene regulating chromatin status could induce changes in the epigenetic status leading to CIN.…”

Section: Discussionmentioning

confidence: 99%

“…Differences in DNA methylation in DAXX mutated tumours compared to control seem to be more pronounced (Fig. 4) (Pipinikas et al 2015). Yet, the tumour pathways associated with DAXX and ATRX loss are not well understood.…”

Section: Pancreatic Netmentioning

confidence: 95%

“…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: 98%

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Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pancreatic Netmentioning

confidence: 95%

Section: Chromatinmentioning

confidence: 98%

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Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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“…In conclusion, since NETs apparently display few relevant mutations, DNA profiling may not help in predicting therapeutic responsiveness. On the other hand, epigenetic approaches may be more relevant since most of the mutated genes are involved in chromatin remodelling (Pipinikas et al 2015).…”

Section: Methodsmentioning

confidence: 99%

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Zatelli¹,

Fanciulli²,

Malandrino³

et al. 2015

Endocrine-Related Cancer

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Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

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Molecular Genetics of Neuroendocrine Tumors

Papadopoulos

Hruban

2018

The Pancreas

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Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours

Cited by 57 publications

References 9 publications

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Molecular Genetics of Neuroendocrine Tumors

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