Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia, United States of America.
Endocr Relat Cancer. 2023 Sep 11;30(10). doi: 10.1530/ERC-23-0067. Print 2023 Oct 1.
Gastrointestinal stromal tumors (GISTs) 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 involved 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 analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess 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 GISTs. 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 ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.
胃肠道间质瘤（GISTs）是一种间叶性肿瘤，被认为起源于卡哈尔间质细胞（ICC），通常由酪氨酸激酶受体（TKR）KIT 或 PDGFRA 的过度表达引起。在这里，我们提供的证据表明，胚胎干细胞因子 FOXD3，最初被鉴定为“创世纪”，并参与胃肠道和神经嵴细胞的发育，与 GIST 的发病机制有关；在体外和斑马鱼以及 FOXD3 缺陷的小鼠模型中都研究了其参与情况。对总共 58 名野生型 GIST 患者的样本进行了分子分析，包括 Sanger 测序、比较基因组杂交和甲基化分析。免疫组织化学和 Western blot 评估用于评估 FOXD3 的表达。此外，我们还进行了组织样本和转染细胞的体外功能研究，以确认鉴定的遗传变异的致病性。在孤立性 GIST 患者中发现了 FOXD3 的胚系部分失活序列变异（p.R54H 和 p.Ala88_Gly91del）。肿瘤中最常见的染色体异常是 1p 染色体缺失。体外实验表明，这些变异存在时 FOXD3 的功能受损。动物研究表明，GI 神经网络被破坏，ICC 的数量和分布发生变化。FOXD3 抑制人类细胞中的 KIT 表达；其失活导致斑马鱼和小鼠 ICC 增加，为 FOXD3 缺陷与 KIT 过度表达导致 GIST 形成之间的功能联系提供了证据。
