p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Sekiya, Tomoko; Bronstein, Marcello D.; Benfini, Katiuscia; Longuini, Viviane C.; Jallad, Raquel S.; Machado, Márcio Carlos; Gonçalves, Tatiana; Osaki, Luciana H.; Higashi, Leonardo; Viana-Jr, Jose; Kater, Cláudio E.; Lee, Misu; Molatore, Sara; Francisco, Guilherme; Chammas, Roger; Naslavsky, Michel Satya; Schlesinger, David; Gama, Patrı́cia; Duarte, Yeda A. O.; Lebrão, Maria Lúcia; Zatz, Mayana; Meirelles, Osorio; Liberman, Bernardo; Fragoso, Maria Candida Barisson Villares; Toledo, S. P. A.; Pellegata, Natalia S.; Toledo, Rodrigo A.

doi:10.1530/erc-13-0486

Cited by 21 publications

(11 citation statements)

References 30 publications

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“…One case of corticotrophinoma with GNAS mutation was described in a patient with McCune-Albright syndrome (16). A CDKN1B variant has been observed in corticotrophinomas in a large cohort of sporadic pituitary adenomas (17). Similarly, CD is rarely found in the context of familial isolated pituitary adenomas (FIPA) that describes the familial occurrence of isolated pituitary adenomas caused by germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations in 20% of cases (18).…”

Section: Genetic Events In CDmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

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Section: Genetic Events In CDmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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“…An association between the p27 rs2066827 (V109G) polymorphism and corticotroph tumours was found in a large cohort of 447 Brazilian patients affected by different endocrine tumours, including 91 corticotropinomas …”

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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“…Copy number changes which would not be detected by exome sequencing have been observed using CGH arrays [168,169]. There have also been association studies linking increased MTC risk to genes associated with cell cycle regulation [170,230,231,184], although they are not universally positive [231]. These observations fit well with a newer model suggesting heterozygous gene loss is sufficient to drive cancer [227,226].…”

Section: Considering Mechanisms Of C-cell Tumor Initiation and Promentioning

confidence: 57%

Thyroid C-Cell Biology and Oncogenic Transformation

Cote

Grubbs

Hofmann

2015

Medullary Thyroid Carcinoma

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The thyroid parafollicular cell, or commonly named “C-cell,” functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of Rb1 regulatory pathway as potential mediators of C-cell transformation. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation will help in the development of novel molecular targeted therapies.

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p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Cited by 21 publications

References 30 publications

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Genetics of Cushing's disease

Thyroid C-Cell Biology and Oncogenic Transformation

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