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In this study we aimed to elucidate the molecular mechanisms underlying this heterogeneity of ADM PanNETs by integrating transcriptomic (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200936) and DNA methylation (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200993) data. First, DNA methylation discriminates ADM-PanNET from PanNET mutated only in\n                    <jats:italic>MEN1<\/jats:italic>\n                    (\u03b1-like), revealing enhancer, peri-centromeric, and telomeric methylation changes associated with alternative lengthening of telomeres and increased chromosomal instability. Transcriptomic analysis further revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. Notably, the ADM immunosuppressive subtype, although significantly smaller (&lt;\u20092.5\u00a0cm,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.023), exhibits strong immune and metastasis-like signatures, suggesting a uniquely aggressive biology despite its reduced size. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1007\/s12022-025-09889-6","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T05:49:34Z","timestamp":1762753774000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular Subtypes of Pancreatic Neuroendocrine Tumors Mutated in MEN1\/DAXX\/ATRX Explain Biological Variability"],"prefix":"10.1007","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-7919","authenticated-orcid":false,"given":"Simona","family":"Avanthay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annunziata","family":"Di Domenico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-2318","authenticated-orcid":false,"given":"Philipp","family":"Kirchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3966-3579","authenticated-orcid":false,"given":"Konstantin","family":"Br\u00e4utigam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8812-6788","authenticated-orcid":false,"given":"Aziz","family":"Chouchane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renaud","family":"Maire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3962-5780","authenticated-orcid":false,"given":"Christina","family":"Thirlwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina","family":"Kim-Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6819-6092","authenticated-orcid":false,"given":"Aurel","family":"Perren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-6636","authenticated-orcid":false,"given":"Ilaria","family":"Marinoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"9889_CR1","doi-asserted-by":"crossref","unstructured":"Maharjan CK, Ear PH, Tran CG, et al (2021) Pancreatic neuroendocrine tumors: Molecular mechanisms and therapeutic targets. 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