胃肠间质瘤（GIST）是一种间叶细胞肿瘤，据信起源于Cajal间质细胞（ICC），通常由酪氨酸激酶受体（TKR）KIT或PDGFRA的过表达引起。本文提供证据表明，最初被鉴定为“Genesis”并在胃肠道和神经嵴细胞发育中发挥作用的胚胎干细胞因子FOXD3参与了GIST的发病机制；我们在体外、斑马鱼和FOXD3缺陷的小鼠模型中对其进行了研究。使用来自58名野生型GIST患者的样本进行了分子分析，包括sanger序列、CGH和甲基化。免疫组织化学和免疫印迹评估用于检测FOXD3的表达。此外，我们进行了体外功能研究，以验证已鉴定的遗传变异的致病性。结果发现在孤立性GIST患者中发现了部分失活的FOXD3序列变异（p.R54H和p.Ala88_Gly91del）。染色体1p缺失是最常见的染色体异常。体外实验表明这些变异会损害FOXD3的功能。动物实验显示GI神经网络受到破坏，并改变了ICC的数量和分布。FOXD3抑制人类细胞中KIT的表达；FOXD3失活导致斑马鱼和小鼠中ICC数量增加，为FOXD3缺陷与KIT过表达导致GIST形成的功能联系提供了证据。

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as "Genesis" and functioning in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analysis, including sanger sequence, CGH and methylation. Immunohistochemistry and Western blot evaluation were used to access FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GIST. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICCs in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.