Distinct epigenetic aging in sporadic and hereditary neuroendocrine neoplasms

Epigenetic clocks assess DNA aging based on DNA methylation. We aimed to study the utility of methylation clocks in understanding the distinct characteristics of sporadic and hereditary neuroendocrine neoplasms (NEN).

Epigenetic age and acceleration were calculated based on Horvath multi-tissue, Levine, and Hannum clocks, and compared by genetic predisposition and NEN grading (WHO-defined G1, G2 and G3).

Following quality assessment and filtering of the data, 93/96 samples were analyzed. Of them, 41/93, 42/93, and 10/93 were sporadic, multiple endocrine neoplasia 1 (MEN1) and von Hippel-Lindau (VHL)-related NEN, respectively. Forty-eight (48/93) were pancreatic NEN (PanNEN). mDNA age positively correlated with chronological age based on three different clock algorithms, but stronger correlations were found in the hereditary NEN subgroups (Horvath clock, r = 0.65, p < 0.001 for MEN1-relatd NEN, and r = 0.86, p = 0.002 in VHL-related NEN). Epigenetic age acceleration was higher in sporadic NEN compared to hereditary NEN, both based on chronological age-adjusted epigenetic age (Hannum clock, sporadic vs. MEN, p = 0.03; sporadic vs. VHL, p = 0.0002), and based on the difference between epigenetic age and chronological age (Hannum clock, sporadic vs. MEN1, p = 0.009; sporadic vs. VHL, p = 0.0005). Finally, epigenetic age (p = 0.04) and age acceleration (p = 0.03) were higher among adult patients with NEN (G2/3 vs. G1).

Epigenetic age and age acceleration analysis demonstrate distinct patterns in sporadic and hereditary NEN, suggesting lower impact of epigenetic alteration or DNA aging in the pathogenesis of hereditary NEN.