Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors

Fabio R. Faucz, 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.
Anelia D. Horvath, Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia, United States of America.
Guillaume Assié, Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France.
Madson Q. Almeida, 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.
Eva Szarek, 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.
Sosipatros Boikos, 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.
Anna Angelousi, 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.
Isaac Levy, 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.
Andrea G. Maria, 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.
Ajay Chitnis, Laboratory of Molecular Genetics, Section on Neural Developmental Dynamics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Cristina R. Antonescu, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Rainer Claus, Hematology and Oncology, Medical Faculty, University of Augsburg, Augsburg, Germany.
Jérôme Bertherat, Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France.
Christoph Plass, Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany.
Charis Eng, Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Constantine A. Stratakis, 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.

Document Type

Journal Article

Publication Date

10-1-2023

Journal

Endocrine-related cancer

Volume

30

Issue

10

DOI

10.1530/ERC-23-0067

Keywords

Carney triad; Carney–Stratakis syndrome; FOXD3; GIST; interstitial cells of Cajal

Abstract

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.

Department

Biochemistry and Molecular Medicine

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