Screening for GPR101 defects in pediatric pituitary corticotropinomas

Trivellin, Giampaolo; Correa, Ricardo; Batsis, Maria; Faucz, Fábio R.; Chittiboina, Prashant; Bjelobaba, Ivana; Larco, Darwin O.; Quezado, Martha; Daly, Adrian; Stojilković, Stanko S.; Wu, Tao; Beckers, Albert; Lodish, Maya; Stratakis, Constantine A.

doi:10.1530/erc-16-0091

Cited by 27 publications

(14 citation statements)

References 22 publications

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“…It is relatively rare and its role in pituitary pathogenesis is unknown (13,126,135,136,137). Other missense variants have been detected in prolactinomas and corticotropinomas with unknown impact on tumorigenesis (137,138).…”

Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 99%

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Vandeva

Daly

Pétrossians

et al. 2019

European Journal of Endocrinology

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Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

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Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 99%

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Vandeva

Daly

Pétrossians

et al. 2019

European Journal of Endocrinology

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“…The resulting USP8 mutants show higher activity than the wild-type and trigger ACTH secretion in pituitary cells through EGFR-dependent signaling (17). It is noteworthy that USP8 mutations represent an exclusive trait of CD and are not detected in any other type of pituitary tumors nor in ACTH-producing tumors of extrapituitary origin (15,16,17,18,19,20). The aim of this study is to investigate the mutational status of USP8 in tumors of patients diagnosed with NS.…”

Section: Introductionmentioning

confidence: 99%

Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor

Pérez-Rivas

Theodoropoulou

Puar

et al. 2018

European Journal of Endocrinology

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“…The search for genetic causes of pituitary tumours led to the discovery of additional genes such as the gene encoding for the orphan G protein‐coupled receptor ( GPR101 ) that shows germline duplication in patients with X‐linked acrogigantism . Screening a cohort of paediatric CD did not reveal germline or somatic GPR101 mutations . GPR101 transcript levels were not deregulated in corticotropinomas compared to the normal pituitary.…”

Section: Introductionmentioning

confidence: 99%

Genetics of Cushing's disease

Albani

Theodoropoulou

Reincke

2017

Clinical Endocrinology

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SummaryCushing's disease (CD) is a rare disabling condition caused by Adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary. The majority of corticotropic adenomas are monoclonal and occur sporadically. Only rarely does CD arise in the context of genetic familial syndromes. Targeted sequencing of oncogenes and tumour suppressor genes commonly mutated in other tumours did not identify recurrent mutations. In contrast, next generation sequencing allowed us recently to clarify the genetic basis of CD: we identified somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene in a significant portion of corticotropinomas. These mutations represent a novel and unique mechanism leading to ACTH excess. Inhibition of USP8 or its downstream signalling pathways could represent a new therapeutic approach for the management of CD. In this review, we will focus on this new evidence and its implication for clinical care of affected patients. K E Y W O R D SAdrenocorticotropic hormone, corticotropinoma, cortisol, Cushing's syndrome, mutation, pituitary adenoma | INTRODUCTIONCushing′s disease (CD) is a rare devastating condition leading to chronic hypercortisolism. It is caused by Adrenocorticotropic hormone (ACTH)-secreting tumours (corticotropinomas) of the pituitary gland. With an incidence of 1.2-1.7 cases per million per year, its epidemiology is consistent with a classical rare disease.1 CD is associated with increased morbidity and mortality, the latter mainly due to cardiovascular events. 2Pituitary adenomas are mainly monoclonal neoplasms.3 The genetic basis of CD was unclear until recently when recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8)were identified in almost half of corticotropinomas. 4-8 Based on this evidence, the pathophysiology of CD has become much clearer. In addition, identification of driver mutations opens up novel diagnostic and therapeutic options for CD. Abbreviations which are used throughout the text are defined in the appendix at the end of the article. | Mechanisms of tumorigenesisCorticotropinomas are characterized by altered expression of proteins regulating cell cycle progression. Overexpression of several cyclins has been frequently documented in pituitary adenomas, with overexpression of cyclin E (CCNE1) being specific for corticotropinomas. 9In contrast, cyclin-dependent kinase inhibitors such as p16/Ink4a and p27/Kip1 are downregulated in these tumours. [10][11][12] In particular, p27/ Kip1 protein is dramatically reduced in the majority of corticotropinomas.13 None of the factors that regulate p27 translation and could explain its downregulation at protein but not transcript level, such as dyskeratosis congenita (DKC1)/Dyskerin, ribosomal protein S13 (RPS13), miR221 and miR222, are deregulated in corticotropinomas.14 A recent study using quantitative real time PCR showed decreased transcripts for cyclin D1 and CCNE1 and increased for p16/Ink4 in the 10 CD tumours compared to 11 silent corticotropinomas and 22 n...

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Screening for GPR101 defects in pediatric pituitary corticotropinomas

Cited by 27 publications

References 22 publications

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor

Genetics of Cushing's disease

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