PUBLICATION
Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors
- Authors
- Faucz, F.R., Horvath, A.D., Assié, G., Almeida, M.Q., Szarek, E., Boikos, S., Angelousi, A., Levy, I., Maria, A.G., Chitnis, A., Antonescu, C., Claus, R., Bertherat, J., Plass, C., Eng, C., Stratakis, C.A.
- ID
- ZDB-PUB-230815-45
- Date
- 2023
- Source
- Endocrine-related cancer 30(10): (Journal)
- Registered Authors
- Chitnis, Ajay
- Keywords
- none
- MeSH Terms
-
- Animals
- Comparative Genomic Hybridization
- Embryonic Stem Cells/chemistry
- Embryonic Stem Cells/metabolism
- Embryonic Stem Cells/pathology
- Forkhead Transcription Factors/genetics
- Gastrointestinal Neoplasms*/genetics
- Gastrointestinal Stromal Tumors*/genetics
- Humans
- Mice
- Mutation
- Proto-Oncogene Proteins c-kit/genetics
- Receptor, Platelet-Derived Growth Factor alpha/genetics
- Stem Cell Factor/genetics
- Transcription Factors/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37578265 Full text @ Endocr. Relat. Cancer
Citation
Faucz, F.R., Horvath, A.D., Assié, G., Almeida, M.Q., Szarek, E., Boikos, S., Angelousi, A., Levy, I., Maria, A.G., Chitnis, A., Antonescu, C., Claus, R., Bertherat, J., Plass, C., Eng, C., Stratakis, C.A. (2023) Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors. Endocrine-related cancer. 30(10):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping