{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:28:30Z","timestamp":1789021710741,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"4-5","license":[{"start":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T00:00:00Z","timestamp":1716595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011941","name":"Gobierno del Principado de Asturias","doi-asserted-by":"publisher","award":["IDI\/2021\/00079"],"award-info":[{"award-number":["IDI\/2021\/00079"]}],"id":[{"id":"10.13039\/100011941","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI20\/01754"],"award-info":[{"award-number":["PI20\/01754"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    gene methylation within the context of GEP\u2010NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    in 29% of GEP\u2010NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi\u2010center GEP\u2010NEN cohorts. Mechanistic analysis revealed that\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    hypermethylation was not associated with\n                    <jats:italic>SDH<\/jats:italic>\n                    mutations or protein loss, indicating an SDH\u2010independent epigenetic mechanism. Clinically,\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    hypermethylation exhibited a strong correlation with\n                    <jats:italic>TP53<\/jats:italic>\n                    somatic mutations, a hallmark of NEC, its predictive value surpassed that of\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83\u20131.0) for discriminating GI\u2010NECs from GI\u2010NETs, highlighting its superior predictive performance. In conclusion, our findings position\n                    <jats:italic>PCDHGC3<\/jats:italic>\n                    methylation status as a promising molecular biomarker for effectively stratifying patients with GI\u2010NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. \u00a9 2024 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6291","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T11:06:45Z","timestamp":1716635205000},"page":"418-428","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<scp>\n                      <i>PCDHGC3<\/i>\n                    <\/scp>\n                    hypermethylation as a potential biomarker of intestinal neuroendocrine carcinomas"],"prefix":"10.1002","volume":"263","author":[{"given":"Tamara","family":"Cubiella","sequence":"first","affiliation":[{"name":"Health 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Universitario de Cabue\u00f1es  Gij\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iv\u00e1n","family":"Fern\u00e1ndez\u2010Vega","sequence":"additional","affiliation":[{"name":"Department of Pathology Hospital Universitario Central de Asturias  Oviedo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Montero\u2010Pav\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pathology Hospital Universitario Central de Asturias  Oviedo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario F","family":"Fraga","sequence":"additional","affiliation":[{"name":"Health Research Institute of the Principado de Asturias (ISPA)  Oviedo Spain"},{"name":"Institute of Oncology of the Principado de Asturias University of Oviedo  Oviedo Spain"},{"name":"Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC)  El Entrego Spain"},{"name":"Spanish Biomedical 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