Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

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Cushing’s disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene USP8 occur in 35–62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.

The recenT paradigm for managing acromegaly includes microsurgery or endoscopic surgery (transsphenoidal surgery or craniotomy), pharmacological therapy (somatostatin analogue, growth hormonereceptor antagonist, dopamine receptor agonists) and radiosurgery which reverse excessive growth hormone (GH) secretion, and shrink or ablate tumors without compromising normal pituitary function. Maximal control of GH level, reduction of systemic complications and mortality, control of tumor growth, preservation of pituitary function, and extension of life expectancy are the aims of disease management. But these Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study Abstract. Therapeutic effects of presurgical long-acting octreotide treatment on tumor shrinkage, and short-and long-term postoperative GH and IGF-1 levels of acromegaly patients with invasive pituitary macroadenomas were investigated prospectively in Huashan Hospital, Shanghai, China. Thirty-nine untreated acromegaly patients, all with invasive pituitary macroadenomas, were randomly divided into two groups: experimental group (n=19), and control group (n=20). Patients in the experimental group received a three-month course of long-acting octreotide treatment before transsphenoidal surgery; the control group underwent surgery directly. Tumor shrinkage after drug treatment and short-and long-term postoperative GH and IGF-1 levels were analyzed in the two groups. Long-acting octreotide treatment reduced tumor size from 7893 ± 6450 to 4794 ± 4682 mm 3 . Mean shrinkage rate was 37.4 ± 30.9%. GH and IGF-1 levels of the experimental group were lower than the control group at 3 months, 6 months after surgery, and after long-term follow-up. Remission rate (both GH and IGF-1 normal) of the experimental group was higher at 3 and 6 months follow-up, but exhibited no advantage in longterm follow-up. In the experimental group, the total resection rate was higher in patients whose Hardy-Knosp grading decreased to ≤ 2 than those whose Hardy-Knosp grading is still ≥ 3 after drug pretreatment. In conclusion, presurgical long-acting octreotide treatment effectively reduces tumor size and invasion, which helps enhance early remission rates of invasive macroadenomas by transsphenoidal surgery, but does not appear to improve the long-term cure rate.

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The PoleStar N20 low-field iMRI navigation system is a promising tool for safe, minimally invasive, endonasal, transsphenoidal pituitary macroadenomas resection. It enables neurosurgeons to control the extent of tumor resection, particularly for suprasellar tumors, ensuring surgical accuracy and safety, and leading to a decreased likelihood of repeat surgeries. However, this technology is still not satisfying in estimating the amount of the parasellar residual tumor invading into cavernous sinus, given the false or uncertain images generated by low-field iMRI in this region, which are difficult to discriminate between tumor remnant and blood within the venous sinus.

Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 × 10). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.

BackgroundWe aim to study surgical technique and analyze the related factors affecting tumor total removal and postoperative endocrinological remission for endoscopic endonasal pituitary adenomas surgery.MethodsWe retrospectively analyzed 178 endoscopic endonasal pituitary adenomas surgery from March 2011 to May 2014. Endonasal approach included the routine transnasal-sphenoidal approach, transnasal- maxillary sinus approach in four cases and transnasal-clivus approach in one case.ResultsAccording to postoperative imaging data and endocrine examination results, total removal was achieved in 129 patients (72.5%), and endocrinological remission was achieved in 38 patients with functional adenomas (44.1%). Statistical analysis of the clinical data showed that total removal rate was much closely related to tumor volume (P = 0.006), and tumor invasiveness (P < 0.001).ConclusionsIn this study, we found tumor sizes and invasion of cavernous sinus were related to total removal rate and endocrinological remission rate; the direction and degree of tumor invasion, and the surgeon’s experience were the key influence factors of the endocrinological remission rate for invasive functional pituitary adenomas.