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Therefore, we performed whole genome and transcriptome analysis of 39 well differentiated siNET samples. Our genomic data revealed a lack of recurrent driver mutations and demonstrated that multifocal siNETs from individual patients can arise genetically independently. We detected germline mutations in Fanconi anemia DNA repair pathway (FANC) genes, involved in homologous recombination (HR) DNA repair, in 9% of patients and found mutational signatures of defective HR DNA repair in late-stage tumor evolution. Furthermore, transcriptomic analysis revealed low expression of the transcriptional repressor REST. Summarizing, we identify a novel common transcriptomic signature of siNETs and demonstrate that genomic alterations alone do not explain initial tumor formation, while impaired DNA repair likely contributes to tumor evolution and represents a potential pharmaceutical target in a subset of patients.<\/jats:p>","DOI":"10.1038\/s41598-025-01912-4","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T09:03:53Z","timestamp":1747991033000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Small intestinal neuroendocrine tumors lack early genomic drivers, acquire DNA repair defects and harbor hallmarks of low REST expression"],"prefix":"10.1038","volume":"15","author":[{"given":"Felix","family":"Bolduan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"M\u00fcller-B\u00f6tticher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Debnath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Eichhorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Giesecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Wetzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashwat","family":"Sahay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Zemojtel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten","family":"Jaeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Ungethuem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Roderburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina Alisa","family":"Kunze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Horst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Eils","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"Wiedenmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sigal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8426-901X","authenticated-orcid":false,"given":"Naveed","family":"Ishaque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"issue":"7","key":"1912_CR1","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.annonc.2020.03.304","volume":"31","author":"M Pavel","year":"2020","unstructured":"Pavel, M. et al. 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