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Maria Fleseriu, Amir H Hamrahian, Andrew R Hoffman, Daniel F Kelly, Laurence Katznelson
Recurrence of hypercortisolemia after initial treatment of Cushing disease (CD) is more common than previously thought, with a third of patients suffering a recurrence over their lifetime. Awareness of this high rate and delayed timeline (sometimes decades) of potential recurrence is critical and patients with CD should be monitored at regular intervals throughout their lives. In this manuscript, we review the complex evaluation needed for defining CD remission versus persistent disease after surgery, and focus on challenges in diagnosing early recurrent hypercortisolemia...
December 2016: Endocrine Practice
D A Vassiliadi, M Balomenaki, A Asimakopoulou, E Botoula, M Tzanela, S Tsagarakis
CONTEXT: Cushing's disease (CD) has a significant relapse rate after successful transsphenoidal surgery (TSS). Many CD patients respond aberrantly to the desmopressin test (DT). Disappearance of this response after surgery may suggest complete removal of abnormal corticotrophs and a lower possibility of recurrence. OBJECTIVE: The utility of postoperative DT to predict long-term outcome compared to the widely used postoperative cortisol level. DESIGN: Retrospective analysis...
December 2016: Journal of Clinical Endocrinology and Metabolism
Kyohei Hayashi, Naoko Inoshita, Kohei Kawaguchi, Arif Ibrahim Ardisasmita, Hisanori Suzuki, Noriaki Fukuhara, Mitsuo Okada, Hiroshi Nishioka, Yasuhiro Takeuchi, Masayuki Komada, Akira Takeshita, Shozo Yamada
CONTEXT: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. OBJECTIVE: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. SUBJECTS AND METHODS: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry...
February 2016: European Journal of Endocrinology
Silviu Sbiera, Timo Deutschbein, Isabel Weigand, Martin Reincke, Martin Fassnacht, Bruno Allolio
Cushing's disease (CD) is caused by corticotropin-secreting pituitary adenomas and results in substantial morbidity and mortality. Its molecular basis has remained poorly understood until the past few years, when several proteins and genes [such as testicular orphan nuclear receptor 4 (TR4) and heat shock protein 90 (HSP90)] were found to play key roles in the disease. Most recently, mutations in the gene of ubiquitin-specific peptidase 8 (USP8) increasing its deubiquination activity were discovered in a high percentage of corticotroph adenomas...
October 2015: Trends in Endocrinology and Metabolism: TEM
Chuanxin Huang, Yongyong Shi, Yao Zhao
No abstract text is available yet for this article.
July 30, 2015: Oncotarget
Fangfang Jian, Yanan Cao, Liuguan Bian, Qingfang Sun
Cushing's disease (CD), caused by an adrenocorticotropin-secreting pituitary adenoma, leads to hypercortisolemia and causes serious morbidity and increased mortality when suboptimally treated. Currently, the genetic events have rarely been reported in this disease. Recently, the recurrent activating mutations in the gene encoding ubiquitin-specific protease 8 (USP8) in CD have been independently reported by two teams. These hotspot mutations sustain epidermal growth factor receptor (EGFR) signaling and expand the pathogenic role of USP8 in corticotroph adenoma...
November 2015: Endocrine
Marily Theodoropoulou, Martin Reincke, Martin Fassnacht, Masayuki Komada
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...
October 2015: European Journal of Endocrinology
Luis G Perez-Rivas, Marily Theodoropoulou, Francesco Ferraù, Clara Nusser, Kohei Kawaguchi, Constantine A Stratakis, Fabio Rueda Faucz, Luiz E Wildemberg, Guillaume Assié, Rudi Beschorner, Christina Dimopoulou, Michael Buchfelder, Vera Popovic, Christina M Berr, Miklós Tóth, Arif Ibrahim Ardisasmita, Jürgen Honegger, Jerôme Bertherat, Monica R Gadelha, Felix Beuschlein, Günter Stalla, Masayuki Komada, Márta Korbonits, Martin Reincke
CONTEXT: We have recently reported somatic mutations in the ubiquitin-specific protease USP8 gene in a small series of adenomas of patients with Cushing's disease. OBJECTIVE: To determine the prevalence of USP8 mutations and the genotype-phenotype correlation in a large series of patients diagnosed with Cushing's disease. DESIGN: We performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph adenomas using Sanger sequencing...
July 2015: Journal of Clinical Endocrinology and Metabolism
Ursula B Kaiser
The pathogenesis of Cushing's disease is poorly understood; two recent reports identifying somatic mutations in USP8 in pituitary corticotroph tumors provide exciting advances in this field. These mutations alter EGFR trafficking and signaling, raising the prospect that EGFR inhibitors may move the treatment of this disease into the era of precision medicine.
June 2015: Cell Research
Martin Reincke, Silviu Sbiera, Akira Hayakawa, Marily Theodoropoulou, Andrea Osswald, Felix Beuschlein, Thomas Meitinger, Emi Mizuno-Yamasaki, Kohei Kawaguchi, Yasushi Saeki, Keiji Tanaka, Thomas Wieland, Elisabeth Graf, Wolfgang Saeger, Cristina L Ronchi, Bruno Allolio, Michael Buchfelder, Tim M Strom, Martin Fassnacht, Masayuki Komada
Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling...
January 2015: Nature Genetics
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