Neuroendocrine tumours: cracking the epigenetic code

Abstract

The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate genedriven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.

Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors

“…4, 9, 12, 13 Furthermore, sporadic and familial PNETs have mutations of chromatin remodelling genes including death domain-associated protein ( DAXX ) and alpha thalassemia/mental retardation syndrome X-linked ( ATRX ), 14 and sporadic BNETS have alterations of histone residues as well as increased expression of the histone methyltransferase enhancer of zeste homolog 2 ( EZH2 ). 15 These findings suggested that inhibitors targeting epigenetic pathways, may help in altering pro-oncogenic pathways in PNETs and BNETs, and we therefore assessed their in vitro and in vivo effects on NET proliferation and apoptosis.…”

Rethinking pheochromocytomas and paragangliomas from a genomic perspective

“…80 Notably, alterations of MLL2, MLL3 and ATRX are also frequently found in other tumors of neural crest origin. 71,75,76,[81][82][83][84][85] Other interesting genes mutated in two samples and playing a potential role in tumor progression include NRK and ALK, both of which encode protein kinases that are overexpressed in metastatic tissue 76,86 and FMR1 (Fragile X Mental Retardation 1), which is involved in EMT. 87 Other genes with no known role in cancer were also identified including CLPTM1L (overexpressed in cisplatinresistant cell lines), SYNE1 (required for neuronal migration), CAPN2 (required for cytoskeletal remodeling), the putative E3 ubiquitin-protein ligase RFPL4A (RET finger protein-like 4A) and NRX3 (involved in cell adhesion with potential role in angiogenesis).…”

Other Novel Therapies: Biomarkers, microRNAs and microRNA Inhibitors, DNA Methylation, Epigenetics, Immunotherapy and Virotherapy

“…A growing number of potential oncogenic and suppressor miRNAs have been identified and specific miRNA signatures might be used to predict the clinical outcome of pancreatic [13] , lung [14,15] and, more recently, small intestinal NETs [16,17] . Bioinformatic analysis and advanced molecular biology methods might be used to identify specifically and differentially expressed miRNAs, which may be developed as novel biomarkers and therapeutic molecular targets for GEP-NETs [18,19] .…”

“…This suggests that methylation at the CDKN2A promoter may be an early occurrence in gastrinoma tumorigenesis. Conversely, insulinomas have a low frequency (17%) of hypermethylation at CDKN2A [19] .…”