Bolduan Felix, Müller-Bötticher Niklas, Debnath Olivia, Eichhorn Ines, Giesecke Yvonne, Wetzel Alexandra, Sahay Shashwat, Zemojtel Tomasz, Jaeger Marten, Ungethuem Ute, Roderburg Christoph, Kunze Catarina Alisa, Lehmann Annika, Horst David, Tacke Frank, Eils Roland, Wiedenmann Bertram, Sigal Michael, Ishaque Naveed
Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353, Berlin, Germany.
BIH Charité Junior Digital Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Charitéplatz 1, 10117, Berlin, Germany.
Sci Rep. 2025 May 23;15(1):17969. doi: 10.1038/s41598-025-01912-4.
The tumorigenesis of small intestinal neuroendocrine tumors (siNETs) is not understood and comprehensive genomic and transcriptomic data sets are limited. 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.
小肠神经内分泌肿瘤（siNETs）的肿瘤发生机制尚不清楚，全面的基因组和转录组数据集也很有限。因此，我们对39个高分化siNET样本进行了全基因组和转录组分析。我们的基因组数据显示缺乏复发性驱动突变，并表明来自个体患者的多灶性siNETs可能在遗传上独立产生。我们在9%的患者中检测到参与同源重组（HR）DNA修复的范可尼贫血DNA修复途径（FANC）基因的种系突变，并在晚期肿瘤进化中发现了有缺陷的HR DNA修复的突变特征。此外，转录组分析显示转录抑制因子REST的低表达。总之，我们确定了siNETs一种新的常见转录组特征，并证明仅基因组改变不能解释肿瘤的初始形成，而DNA修复受损可能有助于肿瘤进化，并代表了一部分患者的潜在药物靶点。
