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Anna Angelousi 1st Department of Internal Medicine, Unit of Endocrinology, Laikon Hospital, Athens, Greece

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Ploutarchos Tzoulis Department of Metabolism & Experimental Therapeutics, Division of Medicine, University College London, London, UK

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Marina Tsoli 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Eleftherios Chatzellis 251 HAF and VA Hospital, Athens, Greece

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Anna Koumarianou Fourth Department of Internal Medicine, Hematology Oncology Unit, Attikon University Hospital, National and Kapodistrian University of Athens, Greece

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Gregory Kaltsas 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

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Anna Angelousi Endocrine Unit, 1st Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece

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Eva Kassi Endocrine Unit, 1st Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Narjes Ansari-Nasiri Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Harpal Randeva Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK

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Gregory Kaltsas Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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George Chrousos First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Circadian rhythms at a central and peripheral level are operated by transcriptional/translational feedback loops involving a set of genes called ‘clock genes’ that have been implicated in the development of several diseases, including malignancies. Dysregulation of the Clock system can influence cancer susceptibility by regulating DNA damage and repair mechanisms, as well as apoptosis. A number of oncogenic pathways can be dysregulated via clock genes’ epigenetic alterations, including hypermethylation of clock genes’ promoters or variants of clock genes. Clock gene disruption has been studied in breast, lung and prostate cancer, and haematological malignancies. However, it is still not entirely clear whether clock gene disruption is the cause or the consequence of tumourigenesis and data in endocrine neoplasms are scarce. Recent findings suggest that clock genes are implicated in benign and malignant adrenocortical neoplasias. They have been also associated with follicular and papillary thyroid carcinomas and parathyroid adenomas, as well as pituitary adenomas and craniopharyngiomas. Dysregulation of clock genes is also encountered in ovarian and testicular tumours and may also be related with their susceptibility to chemotherapeutic agents. The most common clock genes that are implicated in endocrine neoplasms are PER1, CRY1; in most cases their expression is downregulated in tumoural compared to normal tissues. Although there is still a lot to be done for the better understanding of the role of clock genes in endocrine tumourigenenesis, existing evidence could guide research and help identify novel therapeutic targets aiming mainly at the peripheral components of the clock gene system.

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Anna Angelousi Department of Pathophysiology, Sector of Endocrinology, National & Kapodistrian University of Athens, Athens, Greece

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Georgios K Dimitriadis Division of Translational and Experimental Medicine, University of Warwick Medical School, Clinical Sciences Research Laboratories, Coventry, UK

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Georgios Zografos Third Department of Surgery, Athens General Hospital “Georgios Gennimatas”, Athens, Greece

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Svenja Nölting Department of Internal Medicine II, Campus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany

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Gregory Kaltsas Department of Pathophysiology, Sector of Endocrinology, National & Kapodistrian University of Athens, Athens, Greece
Division of Translational and Experimental Medicine, University of Warwick Medical School, Clinical Sciences Research Laboratories, Coventry, UK
Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK

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Ashley Grossman Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK

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Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

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Georgios K Dimitriadis The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK

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Anna Angelousi Division of Pathophysiology, National and Kapodistrian University of Athens Medical School, Athens, Greece

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Martin O Weickert The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK

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Harpal S Randeva The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK

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Gregory Kaltsas The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK
Division of Pathophysiology, National and Kapodistrian University of Athens Medical School, Athens, Greece
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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Ashley Grossman Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. However, occasionally neoplasms, with or without endocrine differentiation, acquire the ability to secrete a variety of bioactive substances or induce immune cross-reactivity with the normal tissues that can lead to the development of characteristic clinical syndromes. These syndromes are named endocrine paraneoplastic syndromes when the specific secretory components (hormones, peptides or cytokines) are unrelated to the anticipated tissue or organ of origin. Endocrine paraneoplastic syndromes can complicate the patient’s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. These syndromes can precede, occur concomitantly or present at a later stage of tumour development, and along with the secreted substances constitute the biological ‘fingerprint’ of the tumour. Their detection can facilitate early diagnosis of the underlying neoplasia, monitor response to treatment and/or detect early recurrences following successful initial management. Although when associated with tumours of low malignant potential they usually do not affect long-term outcome, in cases of highly malignant tumours, endocrine paraneoplastic syndromes are usually associated with poorer survival outcomes. Recent medical advances have not only improved our understanding of paraneoplastic syndrome pathogenesis in general but also enhanced their diagnosis and treatment. Yet, given the rarity of endocrine paraneoplastic syndromes, there is a paucity of prospective clinical trials to guide management. The development of well-designed prospective multicentre trials remains a priority in the field in order to fully characterise these syndromes and provide evidence-based diagnostic and therapeutic protocols.

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Anna Angelousi Unit of Endocrinology, First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece

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Aimee R Hayes Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK

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Eleftherios Chatzellis Endocrinology Diabetes and Metabolism Department, 251 Hellenic Air Force and VA General Hospital, Athens, Greece

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Gregory A Kaltsas First Department of Propaedeutic Internal Medicine, Laiko Hospital, National & Kapodistrian University of Athens, Athens, Greece

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Ashley B Grossman Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
Green Templeton College, University of Oxford, Oxford, UK
Centre for Endocrinology, Barts and the London School of Medicine, London, UK

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Medullary thyroid carcinoma (MTC) is a rare malignancy comprising 1–2% of all thyroid cancers in the United States. Approximately 20% of cases are familial, secondary to a germline RET mutation, while the remaining 80% are sporadic and also harbour a somatic RET mutation in more than half of all cases. Up to 15–20% of patients will present with distant metastatic disease, and retrospective series report a 10-year survival of 10–40% from time of first metastasis. Historically, systemic therapies for metastatic MTC have been limited, and cytotoxic chemotherapy has demonstrated poor objective response rates. However, in the last decade, targeted therapies, particularly multitargeted tyrosine kinase inhibitors (TKIs), have demonstrated prolonged progression-free survival in advanced and progressive MTC. Both cabozantinib and vandetanib have been approved as first-line treatment options in many countries; nevertheless, their use is limited by high toxicity rates and dose reductions are often necessary. New generation TKIs, such as selpercatinib or pralsetinib, that exhibit selective activity against RET, have recently been approved as a second-line treatment option, and they exhibit a more favourable side-effect profile. Peptide receptor radionuclide therapy or immune checkpoint inhibitors may also constitute potential therapeutic options in specific clinical settings. In this review, we aim to present all current therapeutic options available for patients with progressive MTC, as well as new or as yet experimental treatments.

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Anna Angelousi Endocrine Unit, 1st Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece

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Krystallenia I Alexandraki Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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George Kyriakopoulos Department of Pathology, General Hospital ‘Evangelismos’, Αthens, Greece

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Marina Tsoli Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Dimitrios Thomas Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Gregory Kaltsas Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Ashley Grossman Department of Endocrinology, OCDEM, University of Oxford, Oxford, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK

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Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis.

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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

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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

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Guillaume Assié Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France
Endocrine Department, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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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
Adrenal Unit, Laboratory of Molecular and Cellular Endocrinology LIM/25, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, São Paulo, Brasil

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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

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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

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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

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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

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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

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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

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Cristina R Antonescu Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America

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Rainer Claus Hematology and Oncology, Medical Faculty, University of Augsburg, Augsburg, Germany

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Jérôme Bertherat Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France
Endocrine Department, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Christoph Plass Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany

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Charis Eng Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America

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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
Human Genetics & Precision Medicine, IMBB, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece
Research Institute, ELPEN, Pikermi, Athens, Greece

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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.

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