NETs: organ-related epigenetic derangements and potential clinical applications

Abstract

High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications.

Keywords: ATRX; DAXX; DNA methylation; MEN1; carcinoid tumors.

Figure 1. Epigenetic regulation of gene expression

Epigenetic alterations such as DNA methylation and/or histone modifications modulate the accessibility of genes to the transcriptional machinery by inducing either a relaxed/open or condensed/closed chromatin configuration. miRNAs concur to regulate the cell phenotype by repressing the expression of gene transcripts.

Figure 2. Frequent epigenetic modifications in insulinomas and other pNETs

While the epigenetic landscape of insulinomas is characterized by alterations of the signaling of MLH1 and IGF2, non-insulinoma pNETs are defined by a different pattern of epigenetic changes, eventually leading to cell cycle dysregulation, increased cell motility and chemoresistance.