{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:23:25Z","timestamp":1787163805935,"version":"build-2736575974"},"reference-count":23,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100008765","name":"Soci\u00e9t\u00e9 Nationale Fran\u00e7aise de Gastro-Ent\u00e9rologie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008765","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":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    High\u2010grade neuroendocrine tumors of the small intestine are separated into two groups: well\u2010differentiated neuroendocrine tumors (NETs, high\u2010grade) and poorly differentiated neuroendocrine carcinomas (NECs). They represent very rare entities, with few molecular data available, and are very challenging to treat. In this study we aimed to describe the molecular profile of these tumors and their spatial and temporal heterogeneity. We collected a national multicenter cohort of high\u2010grade NETs (14 patients) and NECs (11 patients). DNA and RNA were extracted and somatic point mutations, copy number variations, and gene expression levels were studied using high\u2010throughput sequencing of a panel of 571 genes and RNA sequencing, respectively. Additional samples to study spatial or temporal heterogeneity were available for 12 patients, leading to a total of 42 samples analyzed. Differential diagnostic markers were confirmed by immunohistochemistry. NECs resemble their counterparts in other organs, with a relatively high tumor mutational burden (TMB) and frequent alteration of\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>RB1<\/jats:italic>\n                    , together with organ\u2010specific alterations such as\n                    <jats:italic>APC<\/jats:italic>\n                    . In contrast, high\u2010grade NETs resemble low\u2010grade NETs, with a low TMB but frequent chromosomic alterations. Transcriptomic analysis confirmed that high\u2010grade NETs and NECs are two distinct entities, with specific drivers. Serotonin pathway markers were the most efficient to discriminate high\u2010grade ileal NETs from NECs. Despite variations in the proliferation index, NETs showed little spatial and temporal heterogeneity, suggesting that epigenetic mechanisms play a crucial role in tumor progression. \u00a9 2025 The Author(s).\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.70004","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T14:45:28Z","timestamp":1766155528000},"page":"215-226","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular alterations in high\u2010grade neuroendocrine tumors of the small intestine"],"prefix":"10.1002","volume":"268","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6913-6673","authenticated-orcid":false,"given":"Agathe","family":"Hercent","sequence":"first","affiliation":[{"name":"Department of Pathology, FHU MOSAIC, Beaujon\u2010Bichat Hospitals, AP\u2010HP Universit\u00e9 Paris\u2010Cit\u00e9  Paris France"},{"name":"Department of Genetics Bichat Hospital (APHP), University of Paris Cit\u00e9  Paris France"},{"name":"INSERM U1149 Centre de Recherche sur l'Inflammation  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Masliah\u2010Planchon","sequence":"additional","affiliation":[{"name":"Pharmacogenomics Department Institut Curie, PSL Research University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cohen","sequence":"additional","affiliation":[{"name":"INSERM U1149 Centre de Recherche sur l'Inflammation  Paris 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Bi\u00e8che","sequence":"additional","affiliation":[{"name":"Pharmacogenomics Department Institut Curie, PSL Research University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"de Mestier","sequence":"additional","affiliation":[{"name":"INSERM U1149 Centre de Recherche sur l'Inflammation  Paris France"},{"name":"Department of Gastroenterology and Pancreatology, FHU MOSAIC, Beaujon Hospital, AP\u2010HP Universit\u00e9 Paris\u2010Cit\u00e9  Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Couvelard","sequence":"additional","affiliation":[{"name":"Department of Pathology, FHU MOSAIC, Beaujon\u2010Bichat Hospitals, AP\u2010HP Universit\u00e9 Paris\u2010Cit\u00e9  Paris France"},{"name":"INSERM U1149 Centre de Recherche sur l'Inflammation  Paris 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