Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease

Hernández-Ramírez, Laura C.; Gam, Ryhem; Valdés, Nuria; Lodish, Maya; Pankratz, Nathan; Balsalobre, Aurélio; Gauthier, Yves; Faucz, Fábio R.; Trivellin, Giampaolo; Chittiboina, Prashant; Lane, John; Kay, Denise M.; Dimopoulos, Aggeliki; Gaillard, Stéphan; Néou, Mario; Bertherat, Jérôme; Assié, Guillaume; Clara, Villa; Mills, James L.; Drouin, Jacques; Stratakis, Constantine A.

doi:10.1530/erc-17-0131

Cited by 72 publications

(59 citation statements)

References 62 publications

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“…Recently, another potential pituitary adenoma predisposition gene has been described -CABLES1 (CDK5 and ABL1 enzyme substrate 1) (OMIM *609194) (212). CABLES1 protein is implicated in negative cell cycle regulation in corticotropes in response to glucocorticoids.…”

Section: Other Germline Conditionsmentioning

confidence: 99%

“…Usually the physiologic adrenal-pituitary negative feedback is disrupted in corticotropinomas and CABLES1 protein expression is often lost (213). Given this background, germline and/or tumor DNA samples from an international cohort of 146 pediatric and 35 adult patients was studied for CABLES1 gene variants or copy number variations (212). Four heterozygous missense variants were found in two pediatric and two young adult Cushing's disease patients.…”

Section: Other Germline Conditionsmentioning

confidence: 99%

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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: Other Germline Conditionsmentioning

confidence: 99%

Section: Other Germline Conditionsmentioning

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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“…CABLES1 was previously shown to maintain p21 protein stability by antagonising its proteasomal degradation (Shi et al 2015), while Cables1-knockout mouse embryonic fibroblasts displayed reduced p27 and p16 expression (Kirley et al 2005), supporting a potential broader role for CABLES1 as a cell cycle regulator. Recently, four patients harbouring potentially pathogenic missense CABLES1 variants were found in a cohort of 181 sporadic patients (2.2%) with Cushing's disease (Hernandez-Ramirez et al 2017a). These variants affected residues located within or in proximity with the predicted cyclin-dependent kinase 3-binding domains of CABLES1.…”

Section: Other Germline Mutations Linked With Pituitary Tumoursmentioning

confidence: 99%

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

Pepe

Korbonits

Iacovazzo

2019

Journal of Endocrinology

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While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15–30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune–Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune–Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.

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“…As CABLES1 stabilizes the cell cycle inhibitors p21/Cip1 and p27/Kip1, its loss may contribute to development of corticotropinomas, by downregulation of p27/kip1 and destabilization of p21/cip1 . Screening a cohort of 146 paediatric and 35 adult patients with CD for CABLES1 gene mutations and copy number variations (CNV) revealed 4 potentially pathogenic missense germline variants in 4 female patients: 2 in young adults and 2 in children, but no loss of heterozygosity (LOH) . Interestingly, all these 4 patients had large corticotropinomas with high Ki‐67 proliferation indices and difficult to manage disease.…”

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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Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease

Cited by 72 publications

References 62 publications

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

Genetics of Cushing's disease

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