Gene mutations in Cushing's disease

Xiong, Qi; Ge, Wei

doi:10.3892/br.2016.729

Cited by 2 publications

(7 citation statements)

References 65 publications

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“…So far, apart from mutated USP8, no other recurrent mutations have been found in CAs 4 , 23 , 38 . Thus, more than half of the CA cases may have a variable genetic background and may be associated with mutations of different single genes or may be caused by epigenetic mechanisms (see below).…”

Section: Genetic and Epigenetic Modifications In Sporadic Corticotropmentioning

confidence: 98%

“…Less than 5% of all CAs are familial adenomas representing rare tumor manifestations in various hereditary endocrine syndromes—multiple endocrine neoplasia 1 (MEN1), MEN4, Carney complex (CNC), and DICER1 syndrome—or in familial isolated pituitary adenomas (FIPAs) 4 , 8 . Patients with MEN1, which is caused by a mutation of the MEN1 gene encoding the tumor suppressor menin, mainly manifest prolactinomas and somatotropinomas and only about 5% of their totality is represented by corticotroph tumors 8 , 9 .…”

Section: Genetics Of Hereditary Corticotroph Adenomasmentioning

confidence: 99%

“…In several studies with big cohorts of patients with sporadic pituitary adenoma, only three cases of pathogenetic AIP mutations and three cases of menin mutations have been found in sporadic corticotropinomas, suggesting that mutations of genes causing hereditary corticotroph tumors play only a minor role in sporadic CA development 4 , 15 , 16 .…”

Section: Genetics Of Hereditary Corticotroph Adenomasmentioning

confidence: 99%

“…Thus, more than half of the CA cases may have a variable genetic background and may be associated with mutations of different single genes or may be caused by epigenetic mechanisms (see below). So far, several mutations of different genes have been described in CAs, which mainly affected cell cycle–regulating proteins, signal transduction proteins, oncogenes, and tumor suppressors 4 , 23 , 38 , 39 . Very recently, loss-of-function mutations of the Cdk5 and ABL enzyme substrate 1 ( CABLES1 ) gene were found in four patients from a cohort of 146 pediatric and 35 adult patients with Cushing’s disease: two in children and two in young adults 40 .…”

Section: Genetic and Epigenetic Modifications In Sporadic Corticotropmentioning

confidence: 99%

“…CAs have rarely been described with hereditary background, and in the vast majority of sporadic CAs, the genetic background is still largely unknown 4 . Whereas silent CAs are immunopositive for adrenocorticotropic hormone (ACTH), but do not manifest biochemical or clinical hypercortisolism 5 , the majority of clinically active CAs secrete excessive amounts of ACTH, causing chronic hypercortisolism due to lack of hypothalamus–pituitary–adrenal (HPA) axis feedback regulation at the level of the CA, leading to manifestations of the clinical features of Cushing’s disease 1 .…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in understanding corticotroph pituitary tumor initiation and progression

2018

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Cushing’s disease is the most frequent form of hypercortisolism and is caused by hypophyseal corticotroph adenomas secreting excessive amounts of adrenocorticotropic hormone. Most of the tumors develop sporadically and only a limited number of corticotroph adenomas have been found to be associated with different neuroendocrine syndromes or with familial isolated pituitary adenomas. The pathogenic mechanisms of corticotroph adenomas are largely unknown, but the discovered aberrant chaperoning activity of heat shock protein 90 on the one hand and the presence of ubiquitin-specific protease 8 mutations on the other hand partially explained the causes of their development. Corticotroph tumors arise initially as benign microadenomas but with time form invasively growing aggressive macroadenomas which can switch to corticotroph carcinomas in extremely rare cases. The mechanisms through which corticotroph tumors escape from glucocorticoid negative feedback are still poorly understood, as are the processes that trigger the progression of benign corticotroph adenomas toward aggressive and malignant phenotypes. This review summarizes recent findings regarding initiation and progression of corticotroph pituitary tumors.

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Section: Genetic and Epigenetic Modifications In Sporadic Corticotropmentioning

confidence: 98%

Section: Genetics Of Hereditary Corticotroph Adenomasmentioning

confidence: 99%

Section: Genetics Of Hereditary Corticotroph Adenomasmentioning

confidence: 99%

Section: Genetic and Epigenetic Modifications In Sporadic Corticotropmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recent advances in understanding corticotroph pituitary tumor initiation and progression

2018

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Recent Understanding and Future Directions of Recurrent Corticotroph Tumors

2021

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Corticotroph tumors (CTs) are pituitary neoplasms arising from the Tpit lineage, which may or not express adrenocorticotrophic hormone (ACTH). Functioning CTs cause Cushing’s disease (CD), which has high morbidity and mortality due to hypercortisolemia. “Non-functioning” or silent CTs (SCT) and the Crooke’s cell subtypes do not cause CD and may be asymptomatic until manifested by compressive symptoms and are more frequently found as macroadenoma. Both tend toward more aggressive behavior, recurrence, and a higher rate of malignant transformation to pituitary carcinoma. Tumorigenesis involves genetic, epigenetic, and post-transcriptional disruption of cell-cycle regulators, which increase cell proliferation, POMC overexpression, ACTH transcription, and/or hypersecretion. Furthermore, functioning CTs develop resistance to glucocorticoid-mediated negative feedback on ACTH secretion, through increased expression of testicular orphan nuclear receptor 4 (TR4), heat-shock protein 90 (HSP90), and loss-of-function mutation of CDK5 and ABL enzyme substrate 1 (CABLES1) gene. Overt autonomous hypercortisolemia is difficult to control, and multiple diagnostic studies and therapeutic modalities are commonly required. Cell-cycle regulation depends mainly on p27, cyclin E, cyclin-dependent kinases (CDKs), and the retinoblastoma protein (Rb)/E2F1 transcription factor complex. Gain-of-function mutations of ubiquitin-specific protease (USP) 8, USP48, and BRAF genes may subsequently cause overexpression of epithelial growth factor receptor (EGFR), and enhance POMC transcription, cell proliferation, and tumor growth. Epigenetic changes through micro RNAs and decreased DNA deacetylation by histone deacetylase type 2 (HDAC2), may also affect tumor growth. All the former mechanisms may become interesting therapeutic targets for CTs, aside from temozolomide, currently used for aggressive tumors. Potential therapeutic agents are EGFR inhibitors such as gefitinib and lapatinib, the purine analog R-roscovitine by dissociation of CDK2/Cyclin E complex, the HSP90 inhibitor silibinin (novobiocin), to reduce resistance to glucocorticoid-mediated negative feedback, and BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E positive tumors. This review summarizes the molecular mechanisms related to CTs tumorigenesis, their diagnostic approach, and provides an update of the potential novel therapies, from the lab bench to the clinical translation.

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Gene mutations in Cushing's disease

Cited by 2 publications

References 65 publications

Recent advances in understanding corticotroph pituitary tumor initiation and progression

Recent advances in understanding corticotroph pituitary tumor initiation and progression

Recent Understanding and Future Directions of Recurrent Corticotroph Tumors

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