{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:47:08Z","timestamp":1789577228792,"version":"build-2803163510"},"reference-count":33,"publisher":"Bioscientifica","issue":"7","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                    <jats:p\/>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Colorectal neuroendocrine carcinoma (NEC) is a rare and aggressive cancer and in a subset of patients associated with an adenocarcinoma (AC) component. When both components exceed 30% of the tumour, it is classified as mixed neuroendocrine\u2013non-neuroendocrine neoplasm (MiNEN), although there is an ongoing debate about whether any presence of two distinct components should be sufficient for a MiNEN diagnosis. This study aimed to investigate the origin and subsequent genetic changes of these two components. Ten colorectal cases suitable for sampling of an AC and a poorly differentiated NEC component were identified from the NORDIC NEC 2 study and sequenced across a 360-cancer gene panel. Mock phylogenetic trees were constructed from the molecular profiles of each sample within a patient. All ten cases revealed a common trunk of shared somatic mutations, including well-known colorectal cancer driver mutations such as BRAF, KRAS, APC, and TP53. In all cases, a single branching point separated the AC and NEC components. Private AC and NEC mutations generally had low variant allele frequencies, indicating that most AC and NEC cells were genetically similar. NEC, when compared with AC samples, demonstrated a higher frequency of private mutations (P = 0.009), indicating a higher mutation rate and greater ploidy (P = 0.012), suggesting an association between genomic duplication and AC-to-NEC transition. Shared mutations indicate a common clonal origin, underscoring the role of established colorectal driver mutations in the early development of these tumours, while the mechanisms underlying NEC differentiation remain poorly understood and may involve non-genetic factors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/erc-26-0170","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T12:02:51Z","timestamp":1783944171000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":1,"title":["Origin and evolution of colorectal mixed neuroendocrine\u2013non-neuroendocrine neoplasms (MiNEN)"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8676-772X","authenticated-orcid":true,"given":"Siren","family":"Morken","sequence":"first","affiliation":[{"name":"Cancer Clinic, Haukeland University Hospital 1 , ,","place":["Bergen, Norway"]},{"name":"Department of Clinical Science, University of Bergen 2 , ,","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halfdan","family":"Sorbye","sequence":"additional","affiliation":[{"name":"Cancer Clinic, Haukeland University Hospital 1 , ,","place":["Bergen, Norway"]},{"name":"Department of Clinical Science, University of Bergen 2 , ,","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Deng","sequence":"additional","affiliation":[{"name":"Cancer Clinic, Haukeland University Hospital 1 , ,","place":["Bergen, Norway"]},{"name":"Department of Clinical Science, University of Bergen 2 , ,","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9853-059X","authenticated-orcid":true,"given":"Hatice Toprak","family":"Dogramaci","sequence":"additional","affiliation":[{"name":"Cancer Clinic, Haukeland University Hospital 1 , ,","place":["Bergen, Norway"]},{"name":"Department of Clinical Science, University of Bergen 2 , ,","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Venizelos","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, University of Bergen 2 , ,","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene","family":"Weber Vestermark","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital of Southern Denmark 3 , ,","place":["Esbjerg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Department of Oncology, Odense University Hospital 4 , ,","place":["Odense, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kersten","sequence":"additional","affiliation":[{"name":"Department of Research, Hospital of Southern Norway 5 , ,","place":["Kristiansand, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurel","family":"Perren","sequence":"additional","affiliation":[{"name":"Institute of Tissue Medicine and Pathology, University of Bern 6 , ,","place":["Bern, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-1655","authenticated-orcid":true,"given":"Stian","family":"Knappskog","sequence":"additional","affiliation":[{"name":"Cancer Clinic, Haukeland University Hospital 1 , ,","place":["Bergen, Norway"]},{"name":"Department of Clinical Science, University of Bergen 2 , ,","place":["Bergen, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"2026072811211251300_bib1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO classification of neuroendocrine neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026072811211251300_bib2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00428-025-04241-z","article-title":"MiNEN, amphicrine carcinomas, and conventional carcinomas with neuroendocrine differentiation: diagnostic criteria, open questions, and future perspectives","volume":"488","author":"Jesinghaus","year":"2026","journal-title":"Virchows Arch"},{"key":"2026072811211251300_bib3","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3390\/jcm9010273","article-title":"Mixed neuroendocrine non-neuroendocrine neoplasms: a systematic review of a controversial and underestimated diagnosis","volume":"9","author":"Frizziero","year":"2020","journal-title":"J Clin Med"},{"key":"2026072811211251300_bib4","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1159\/000475527","article-title":"Digestive system mixed neuroendocrine-non-neuroendocrine neoplasms","volume":"105","author":"de Mestier","year":"2017","journal-title":"Neuroendocrinology"},{"key":"2026072811211251300_bib5","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1111\/his.14178","article-title":"Looking into digestive mixed neuroendocrine - nonneuroendocrine neoplasms: subtypes, prognosis, and predictive factors","volume":"77","author":"Uccella","year":"2020","journal-title":"Histopathology"},{"key":"2026072811211251300_bib6","doi-asserted-by":"crossref","DOI":"10.1111\/jne.13249","article-title":"European neuroendocrine tumor society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma","volume":"35","author":"Sorbye","year":"2023","journal-title":"J Neuroendocrinol"},{"key":"2026072811211251300_bib7","first-page":"177","article-title":"Genetic characteristics of colorectal neuroendocrine carcinoma: more similar to colorectal adenocarcinoma","volume":"20","author":"Chen","year":"2021","journal-title":"Clin Colorectal Cancer"},{"key":"2026072811211251300_bib8","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.1038\/s41598-021-85593-9","article-title":"Comprehensive analysis of mutational and clinicopathologic characteristics of poorly differentiated colorectal neuroendocrine carcinomas","volume":"11","author":"Lee","year":"2021","journal-title":"Sci Rep"},{"key":"2026072811211251300_bib9","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/j.humpath.2015.08.006","article-title":"Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor","volume":"46","author":"Takizawa","year":"2015","journal-title":"Hum Pathol"},{"key":"2026072811211251300_bib10","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1002\/ijc.70367","article-title":"Molecular-clinical characteristics and treatment outcomes in 163 metastatic colorectal neuroendocrine carcinomas with a comparison to colorectal adenocarcinomas","volume":"158","author":"Morken","year":"2026","journal-title":"Int J Cancer"},{"key":"2026072811211251300_bib11","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s12022-016-9432-9","article-title":"Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms","volume":"27","author":"La Rosa","year":"2016","journal-title":"Endocr Pathol"},{"key":"2026072811211251300_bib12","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1093\/jnci\/89.19.1448","article-title":"Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas","volume":"89","author":"Vortmeyer","year":"1997","journal-title":"J Natl Cancer Inst"},{"key":"2026072811211251300_bib13","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/modpathol.2016.220","article-title":"Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas","volume":"30","author":"Jesinghaus","year":"2017","journal-title":"Mod Pathol"},{"key":"2026072811211251300_bib14","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/modpathol.2016.150","article-title":"In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components","volume":"30","author":"Woischke","year":"2017","journal-title":"Mod Pathol"},{"key":"2026072811211251300_bib15","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2025.100855","article-title":"Clinicopathologic and molecular analysis of colorectal carcinomas with spectrum of neuroendocrine carcinoma components","volume":"38","author":"Albayrak","year":"2025","journal-title":"Mod Pathol"},{"key":"2026072811211251300_bib16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/ERC-21-0152","article-title":"The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms","volume":"29","author":"Venizelos","year":"2022","journal-title":"Endocr Relat Cancer"},{"key":"2026072811211251300_bib17","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nm.3886","article-title":"Subclonal diversification of primary breast cancer revealed by multiregion sequencing","volume":"21","author":"Yates","year":"2015","journal-title":"Nat Med"},{"key":"2026072811211251300_bib18","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkw520","article-title":"FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing","volume":"44","author":"Shen","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026072811211251300_bib19","doi-asserted-by":"crossref","DOI":"10.1530\/ERC-23-0057","article-title":"Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms","volume":"30","author":"Venizelos","year":"2023","journal-title":"Endocr Relat Cancer"},{"key":"2026072811211251300_bib20","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/s41416-024-02773-w","article-title":"Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms","volume":"131","author":"Elvebakken","year":"2024","journal-title":"Br J Cancer"},{"key":"2026072811211251300_bib21","doi-asserted-by":"crossref","first-page":"5111","DOI":"10.3390\/cancers13205111","article-title":"Neuroendocrine differentiation in conventional colorectal adenocarcinomas: incidental finding or prognostic biomarker?","volume":"13","author":"Konukiewitz","year":"2021","journal-title":"Cancers"},{"key":"2026072811211251300_bib22","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1016\/S1470-2045(16)30297-2","article-title":"Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis","volume":"17","author":"Moran","year":"2016","journal-title":"Lancet Oncol"},{"key":"2026072811211251300_bib23","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1159\/000369071","article-title":"Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract: targeted next-generation sequencing suggests a monoclonal origin of the two components","volume":"100","author":"Scardoni","year":"2014","journal-title":"Neuroendocrinology"},{"key":"2026072811211251300_bib24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1002\/path.5556","article-title":"Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas","volume":"253","author":"Koh","year":"2021","journal-title":"J Pathol"},{"key":"2026072811211251300_bib25","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1097\/01.LAB.0000079006.91414.BE","article-title":"Microallelotyping defines the monoclonal or the polyclonal origin of mixed and collision endocrine-exocrine tumors of the gut","volume":"83","author":"Furlan","year":"2003","journal-title":"Lab Invest"},{"key":"2026072811211251300_bib26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s004280100540","article-title":"Genetic evidence for the multi-step progression of mixed glandular-neuroendocrine gastric carcinomas","volume":"440","author":"Kim","year":"2002","journal-title":"Virchows Arch"},{"key":"2026072811211251300_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2023.112576","article-title":"Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins","volume":"42","author":"Qiu","year":"2023","journal-title":"Cell Rep"},{"key":"2026072811211251300_bib28","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1530\/ERC-17-0557","article-title":"Ki67 proliferative index of the neuroendocrine component drives MANEC prognosis","volume":"25","author":"Milione","year":"2018","journal-title":"Endocr Relat Cancer"},{"key":"2026072811211251300_bib29","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1038\/s41379-020-0579-z","article-title":"Chromosomal and molecular pathway alterations in the neuroendocrine carcinoma and adenocarcinoma components of gastric mixed neuroendocrine-nonneuroendocrine neoplasm","volume":"33","author":"Sun","year":"2020","journal-title":"Mod Pathol"},{"key":"2026072811211251300_bib30","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1097\/PAS.0b013e318242e21c","article-title":"Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers","volume":"36","author":"La Rosa","year":"2012","journal-title":"Am J Surg Pathol"},{"key":"2026072811211251300_bib31","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s12022-025-09869-w","article-title":"Exploring intratumoral heterogeneity in mixed neuroendocrine-nonneuroendocrine neoplasms with spatial transcriptomics: even more diverse than anticipated","volume":"36","author":"Weiss","year":"2025","journal-title":"Endocr Pathol"},{"key":"2026072811211251300_bib32","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2024.100568","article-title":"Distinctive phenotypic and microenvironmental characteristics of neuroendocrine carcinoma and adenocarcinoma components in gastric mixed adenoneuroendocrine carcinoma","volume":"37","author":"Kwak","year":"2024","journal-title":"Mod Pathol"},{"key":"2026072811211251300_bib33","article-title":"Mutation spectrum in liquid versus solid biopsies from patients with advanced gastroenteropancreatic neuroendocrine carcinoma","volume":"7","author":"Knappskog","year":"2023","journal-title":"JCO Precis Oncol"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-26-0170\/521907\/erc-26-0170.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-26-0170\/521907\/erc-26-0170.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:21:22Z","timestamp":1785252082000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/33\/7\/e260170\/77795\/Origin-and-evolution-of-colorectal-mixed"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-26-0170","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"article-number":"e260170"}}