Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms.

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis

Characteristics of patients with Cushing\'s disease due to micro and macrocorticotropinomas associated or not with USP8-mutation: a retrospective review of the literature

Objetivo: A doença de Cushing (DC) é uma condição clínica grave geralmente causada por um microcorticotropinoma (MIC) e 7-20% desses pacientes apresentam um macrocorticotropinoma produtor de ACTH (MAC). Recentemente, mutações somáticas no gene USP8 foram identificadas como uma importante causa genética de DC devido a adenomas hipofisários secretores de ACTH (23% - 62%). Poucas séries relataram a distribuição entre MIC e MAC relacionada à mutação USP8 e à correlação genótipo-fenótipo. Nosso objetivo foi avaliar as mutações USP8 em uma coorte de MIC-MAC a partir do único centro terciário. Métodos: DNA-tumor-tecido foi sequenciado (16 MICs e 33 MACs). Dados clínicos, bioquímicos, de imagem e remissão / recorrência foram avaliados. Analisamos sistematicamente 8 séries publicadas. Resultados: Foram identificadas quatro variantes alélicas patogênicas da USP8 previamente descritas em 13 dos 49 corticotrofinomas (26,5%). Oito foram (61,5%) detectados em MACs. As concentrações do cortisol urinário de pacientes com mutação USP8 foram menores do que os do grupo selvagem (p <= 0,012). A frequência de mutações USP8 entre as séries foi de cerca de 30%, com maior prevalência em pacientes do sexo feminino (p < 0,0001). Nenhum consenso significativo foi identificado entre tipo selvagem e mutação da USP8 em relação aos níveis hormonais; tamanho do tumor e remissão / recorrência entre todas as séries. Conclusão: Nossos dados, bem como a revisão retrospectiva sobre DC associada ou não a mutação em USP8, nos mostram um achado heterogêneo entre as séries publicadas, com várias desvantagens devido à falta de um protocolo sistemático para avaliar esses pacientes. Em conclusão, mais estudos prospectivos multicêntricos em uma força-tarefa trarão informações consistentes sobre a influência da principal causa genética da doença de Cushing, o gene USP8, em relação à apresentação clínico-radiológica e às taxas de remissão / recorrênciaObjective: Cushing\'s disease (CD) is a severe clinical condition generally caused by a microcorticotropinomas (MIC) and 7-20% of these patients present an ACTH-producing macrocorticotropinomas (MAC). Recently, somatic mutations in USP8 gene, were identified as a major genetic cause of CD due to ACTH-secreting pituitary adenomas (23% - 62%). Few series reported the distribution between MIC and MAC related to USP8-mutated and to genotype-phenotype correlation. We aimed to evaluate USP8-mutations in a cohort of MIC-MAC from the unique tertiary center. Methods: DNA-tumor- tissue was sequenced (16 MICs and 33 MACs). Clinical, biochemical, imaging data and remission/recurrence rates were evaluated. We systematically analyzed 8 published series. Results: We identified four USP8pathogenic allelic variants previously described in 13 out of 49 corticotrophinomas (26.5%). Eight were (61.5%) detected in MACs. Urinary cortisol levels of patients with USP8-mutated were lower than wild-type group (p <= 0.012). The frequency of USP8-mutated among the series was around 30% with higher prevalence in female patients (p < 0.0001). No significant consensus was identified between wild-type and USP8-mutated regarding hormonal levels; tumor size and remission/recurrence among all series. Conclusion: Our data as well as the retrospective review about CD associated or not with USP8-mutated show us a heterogeneous finding among the published series with several drawbacks due to lack of a systematic protocol to evaluate these patients. In conclusion, further multicenter prospective studies in a task-force will bring consistent information about the influence of the major genetic cause of Cushing\'s disease, USP8 gene, regarding clinical-radiological presentation and remission/recurrence rate

The Role of gsp Mutations on the Development of Adrenal Cortical Tumors and Adrenal Hyperplasias

Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune Albright syndrome and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors and primary macronodular adrenocortical hyperplasia (PMAH). [1-3]The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. in 1990. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear. [3] PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. in 2003 identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of McCune Albright syndrome. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production. [2, 4] With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion.In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia