Epigenetics and disease progression in neuroendocrine neoplasms

Epigenetic regulation, including DNA methylation, histone modifications, non-coding RNAs, and higher-order chromatin remodeling, plays a central role in the biology of neuroendocrine neoplasms (NENs). Advances in high-throughput profiling have uncovered epigenetic alterations across pheochromocytomas/paragangliomas (PPGLs), gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), lung neuroendocrine neoplasms (LNENs), medullary thyroid carcinoma (MTC), and pituitary NETs (PitNETs). These alterations converge on pathways governing cell cycle control, telomere maintenance, hypoxia signaling, epithelial-mesenchymal transition, and chromatin architecture. Importantly, epigenetic signatures not only mirror genetic backgrounds (eg, SDHx, MEN1, ATRX, RET) but also provide independent layers of prognostic and predictive information. Distinct methylation profiles, histone modification patterns, and deregulated microRNA/long non-coding RNA networks have been consistently linked to tumor aggressiveness, metastatic potential, and therapeutic resistance. The clinical translation of these insights is rapidly evolving. Methylation-based classifiers and circulating epigenetic markers are emerging as promising tools for early diagnosis, risk stratification, and longitudinal monitoring. Moreover, epigenetic pathways represent attractive therapeutic targets, with DNA methyltransferase inhibitors, histone deacetylase inhibitors, and RNA-modifying enzyme modulators under active investigation. However, significant challenges remain, including methodological heterogeneity, small or retrospective cohorts, and the limited functional validation of candidate biomarkers. Future priorities include prospective multi-institutional validation, integration of epigenomics with other molecular layers in multidimensional classifiers, and the application of spatial and single cell approaches to resolve intra-tumoral heterogeneity. Ultimately, epigenetic research has redefined our understanding of NEN pathogenesis and progression, positioning the epigenome as a promising frontier in precision oncology. Through robust validation, epigenetic biomarkers and therapies may transform the clinical management of NENs.