{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:28Z","timestamp":1787028568324,"version":"build-2736575974"},"reference-count":139,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Roma","award":["FRCEMAD 21-25"],"award-info":[{"award-number":["FRCEMAD 21-25"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic neuroendocrine tumors (pNETs) are rare malignancies, accounting for 1\u20132% of pancreatic cancers, with an incidence of \u22641 case per 100,000 individuals annually. Originating from pancreatic endocrine cells, pNETs display significant clinical and biological heterogeneity. Traditional classification based on proliferative grading does not fully capture the complex mechanisms involved, such as oxidative stress, mitochondrial dysfunction, and tumor-associated macrophage infiltration. Recent advances in molecular profiling have revealed key oncogenic drivers, including MEN1 (menin 1), DAXX (death domain\u2013associated protein), ATRX (alpha thalassemia\/mental retardation syndrome X-linked), CDKN1B (cyclin-dependent kinase inhibitor 1B) mutations, chromatin remodeling defects, and dysregulation of the mTOR pathway. Somatostatin receptors, particularly SSTR2, play a central role in tumor biology and serve as important prognostic markers, enabling the use of advanced diagnostic imaging (e.g., Gallium-68 DOTATATE PET\/CT) and targeted therapies like somatostatin analogs and peptide receptor radionuclide therapy (PRRT). Established biomarkers such as Chromogranin A and the Ki-67 proliferation index remain vital for diagnosis and prognosis, while emerging markers, like circulating tumor DNA and microRNAs, show promise for enhancing disease monitoring and diagnostic accuracy. This review summarizes the molecular landscape of pNETs and highlights genomic, transcriptomic, proteomic, and epigenomic factors that support the identification of novel diagnostic, prognostic, and therapeutic biomarkers, ultimately advancing personalized treatment strategies.<\/jats:p>","DOI":"10.3390\/ijms26167814","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T15:53:27Z","timestamp":1755100407000},"page":"7814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Decoding Pancreatic Neuroendocrine Tumors: Molecular Profiles, Biomarkers, and Pathways to Personalized Therapy"],"prefix":"10.3390","volume":"26","author":[{"given":"Linda","family":"Galasso","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Vitale","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1216-0965","authenticated-orcid":false,"given":"Gabriele","family":"Giansanti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Esposto","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Borriello","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Mignini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0658-4310","authenticated-orcid":false,"given":"Alberto","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Zileri Dal Verme","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6230-1779","authenticated-orcid":false,"given":"Antonio","family":"Gasbarrini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5847-1065","authenticated-orcid":false,"given":"Maria Elena","family":"Ainora","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Assunta","family":"Zocco","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1093\/annonc\/mdn351","article-title":"Pancreatic neuroendocrine tumors (PNETs): Incidence, prognosis and recent trend toward improved survival","volume":"19","author":"Halfdanarson","year":"2008","journal-title":"Ann. 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