Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Abstract

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.

Primary renal well‐differentiated neuroendocrine tumour (carcinoid): next‐generation sequencing study of 11 cases

“…NETs are sporadic in the majority of cases, but may be associated with hereditary syndromes (i.e. multiple endocrine neoplasia types 1 and type 2, von Hippel–Lindau syndrome, neurofibromatosis type 1, tuberous sclerosis, Carney complex, hyperparathyroidism–jaw tumour syndrome, and hereditary small‐intestine NET) …”

“…multiple endocrine neoplasia types 1 and type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, tuberous sclerosis, Carney complex, hyperparathyroidism-jaw tumour syndrome, and hereditary small-intestine NET). 65,66 Whole genome sequencing approaches have underlined the very low mutation rate of well-differentiated NET of all organs as compared with other malignancies. 66 Molecular alterations have been among the most studied in pancreatic NETs (PanNETs).…”

“…65,66 Whole genome sequencing approaches have underlined the very low mutation rate of well-differentiated NET of all organs as compared with other malignancies. 66 Molecular alterations have been among the most studied in pancreatic NETs (PanNETs). Several novel germline mutations were described recently.…”

Gastroenteropancreatic Neuroendocrine Tumors

“…The exact sequence of gene mutations capable of driving the development and progression of pNETs is currently unknown. Available evidence suggests that mutations of MEN1 play a key role in tumor initiation, whereas late alterations of DAXX/ATRX seem to be implicated in tumor progression . Loss of DAXX/ATRX expression has been associated with activation of the alternative lengthening of telomeres (ALT) pathway and chromosomal instability, and poor outcomes have been reported for patients with ALT‐positive tumors .…”

“…Available evidence suggests that mutations of MEN1 play a key role in tumor initiation, whereas late alterations of DAXX/ATRX seem to be implicated in tumor progression. 33 Loss of DAXX/ATRX expression has been associated with activation of the alternative lengthening of telomeres (ALT) pathway and chromosomal instability, 34 and poor outcomes have been reported for patients with ALT-positive tumors. [34][35][36] Three distinct molecular subtypes of pNETs recently have been identified: 1) the islet/ insulinoma tumor subtype is characterized by low grade and limited metastatic potential; 2) the metastasis-like primary subtype is characterized by high proliferative activity and aggressive behavior; and 3) the MEN1-like/intermediate subtype shows moderate metastatic potential.…”