Summary
Two studies investigated the use of DNA methylation patterns and sex-specific gene expression in neuroendocrine neoplasms (NEN) and Alzheimer disease, respectively. The first study found that DNA methylation patterns can help identify the site of origin for NEN, including distinguishing primary hepatic NEN from other types. The second study revealed sex-specific gene expression associations with Alzheimer disease neuropathology and cognitive decline, highlighting the need for precision medicine approaches.
Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, molecular pathologist, Sonic Healthcare USA, Rye Brook, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Use of DNA methylation patterns to trace origins of neuroendocrine neoplasms
January 2026—Neuroendocrine neoplasms derive from specialized cells that exhibit characteristics of nerve and endocrine cells. They most commonly arise from the gastrointestinal tract, pancreas, and lungs. However, they have also been found in other primary sites, such as skin, thyroid, and liver. Although the liver is a rare primary site for neuroendocrine neoplasms (NEN), it is the most common site of NEN metastasis. Determining the site of origin of NEN often poses a diagnostic challenge and necessitates thorough clinical and histologic workup. However, this distinction is of paramount importance, as certain therapeutic options are dictated by site of origin. DNA methylation refers to the process of adding methyl groups to DNA, typically at cytosine residues in gene promoter regions. The pattern of hypermethylation and hypomethylation can influence gene expression in cancer cells. But more importantly, the pattern of methylation can act as a fingerprint, allowing the classification of tumors by tumor type and primary site. The authors of this study investigated the use of DNA methylation/epigenetic profiles for determining site of origin for NEN. The study cohort consisted of 212 NEN samples, 15 of which were hepatic NEN from 14 patients treated at Beaujon University Hospital, in Paris, France. Using t-SNE (t-distributed Stochastic Neighbor Embedding) plots for data visualization, the authors identified distinct clusters for Merkel cell NEN, pulmonary neuroendocrine carcinoma, and pulmonary carcinoids, as well as appendiceal, ileal, and pancreatic NEN. Gastric/duodenal and colorectal NEN did not exhibit distinct clusters in the t-SNE plot and, therefore, were combined into the group intestinal NEN, not otherwise specified. Interestingly, hepatic NEN without known primary did not form a separate cluster, instead showing overlap with extrahepatic NEN and NEN liver metastasis, but it was distinguished from a non-NEN neoplastic control group consisting of hepatic carcinoma and colorectal carcinoma samples. To examine whether epigenetic profiles were similar between primary tumor and paired metastasis, the authors analyzed 12 paired samples. Ten of the 12 pairs predictably clustered together, while two pairs diverged, with the differences attributed to tumor progression. Grading and Ki-67 proliferation rate vary among NEN, with higher grade tumors often exhibiting a higher proliferation rate. It was observed that NEN with high proliferation rates (Ki-67 greater than 20 percent) showed distinct separation from NEN with low to intermediate proliferation rates. The authors also considered the role of genomic instability by analyzing copy number alteration. They found some organ-specific alterations, such as a large number of genomic alterations across the genome in hepatic NEN and almost no alterations in appendiceal NEN. Despite the acknowledged limitation of a relatively low proportion of NEN entities being represented in this study, the results suggest that epigenetic profiles can be worthwhile in identifying NEN site of origin and investigating whether there is a unique distinction of primary hepatic NEN.
Goeppert B, Charbel A, Toth R, et al. DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms. Nat Commun. 2025. doi.org/10.1038/s41467-025-65227-8
Correspondence: Dr. Benjamin Goeppert at benjamin.goeppert@rkh-gesundheit.de or Dr. Stephanie Roessler at stephanie.roessler@med.uni-heidelberg.de