Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Piscina, Idoia Martinez de la; Hernández-Ramírez, Laura C; Portillo, Nancy; Gómez-Gila, Ana; Urrutia, I.; Martínez-Salazar, Rosa; García-Castaño, Alejandro; Aguayo, Aníbal; Rica, Itxaso; Gaztambide, Sonia; Faucz, Fabio R.; Keil, Margaret F.; Lodish, Maya; Quezado, Martha; Pankratz, Nathan; Chittiboina, Prashant; Lane, John; Kay, Denise M.; Mills, James L.; Castaño, Luís; Stratakis, Constantine A.

doi:10.3389/fendo.2020.00433

Cited by 9 publications

(7 citation statements)

References 42 publications

(54 reference statements)

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“…Several reports have probed the relation between DICER1 and carcinogenesis (4). LOH as well as a second somatic mutation in the RNase III domain in DICER1 is regularly observed in pituitary blastoma (46). However, its impact on pituitary tumourigenesis needs further research although Cotton et al (47) described a 50-year-old female with a microprolactinoma caused by a DICER1 alteration.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas

Piscina

Najera

Rica

et al. 2021

European Journal of Endocrinology

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Objective: Pituitary adenomas (PA) are rare in young patients and additional studies are needed to fully understand their pathogenesis in this population. We describe the clinical and genetic characteristics of apparently sporadic PA in a cohort of young patients. Design: Clinical and molecular analysis of 235 patients (age ≤30 years) with a PA. Clinicians from several Spanish and Chilean hospitals provided data. Methods: Genetic screening was performed via next-generation sequencing and comparative genomic hybridization array. Clinical variables were compared among paediatric, adolescent (<19 years) and young adults’ (≥19-30 years) cohorts and types of adenomas. Phenotype-genotype associations were examined. Results: Among the total cohort mean age was 17.3 years. Local mass effect symptoms were present in 22.0% and prolactinomas were the most frequent (44.7%). Disease-causing germline variants were identified in 22 individuals (9.3%), more exactly in 13.1% and 4.7% of the populations aged 0-19 and 19-30 years, respectively; genetically positive patients were younger at diagnosis and had larger tumour size. Healthy family carriers were also identified. Conclusions: Variants in genes associated with syndromic forms of PAs were detected in a large cohort of apparently sporadic pituitary tumours. We have identified novel variants in well-known genes and set the possibility of incomplete disease penetrance in carriers of MEN1 alterations or a limited clinical expression of the syndrome. Despite the low penetrance observed, screening of AIP and MEN1 variants in young patients and relatives is of clinical value.

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Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas

Piscina

Najera

Rica

et al. 2021

European Journal of Endocrinology

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“…As germline mutations, MEN1, PRKAR1A, CDKN1B , and AIP genes should be considered as a young age-onset genetic syndrome phenotype ( 64 ). In aggressive pediatric Cushing’s syndrome, the DICER1 gene has been reportedly identified to have a causal role in ACTH-producing pituitary blastoma caused by DICER1 syndrome ( 65 – 67 ) ( Table 1 ). Since DICER1 is an enzyme required for the cleavage of a precursor into mature microRNA, noncoding RNA, including microRNA, are associated with the pathogenesis of pituitary ACTH-producing tumors and their aggressiveness.…”

Section: Molecular Pathologymentioning

confidence: 99%

“…In children, temozolomide treatment for aggressive pituitary adenoma and carcinoma is quite rare, which leads to insufficient treatment data. In limited cases of DICER1 mutations with ACTH-secreting pituitary tumors, the effect of temozolomide has not been clearly shown ( 65 , 124 ). Although there is no established course of treatment because of the paucity of data, the ESE guidelines suggest that temozolomide might be beneficial in adults ( 88 ).…”

Section: Treatmentmentioning

confidence: 99%

Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach

et al. 2021

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Cushing’s disease is a syndromic pathological condition caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) mediated by hypercortisolemia. It may have a severe clinical course, including infection, psychiatric disorders, hypercoagulability, and metabolic abnormalities, despite the generally small, nonaggressive nature of the tumors. Up to 20% of ACTHomas show aggressive behavior, which is related to poor surgical outcomes, postsurgical recurrence, serious clinical course, and high mortality. Although several gene variants have been identified in both germline and somatic changes in Cushing’s disease, the pathophysiology of aggressive ACTHomas is poorly understood. In this review, we focused on the aggressiveness of ACTHomas, its pathology, the current status of medical therapy, and future prospects. Crooke’s cell adenoma (CCA), Nelson syndrome, and corticotroph pituitary carcinoma are representative refractory pituitary tumors that secrete superphysiological ACTH. Although clinically asymptomatic, silent corticotroph adenoma is an aggressive ACTH-producing pituitary adenoma. In this review, we summarize the current understanding of the pathophysiology of aggressive ACTHomas, including these tumors, from a molecular point of view based on genetic, pathological, and experimental evidence. The treatment of aggressive ACTHomas is clinically challenging and usually resistant to standard treatment, including surgery, radiotherapy, and established medical therapy (e.g., pasireotide and cabergoline). Temozolomide is the most prescribed pharmaceutical treatment for these tumors. Reports have shown that several treatments for patients with refractory ACTHomas include chemotherapy, such as cyclohexyl-chloroethyl-nitrosourea combined with 5-fluorouracil, or targeted therapies against several molecules including vascular endothelial growth factor receptor, cytotoxic T lymphocyte antigen 4, programmed cell death protein 1 (PD-1), and ligand for PD-1. Genetic and experimental evidence indicates that some possible therapeutic candidates are expected, such as epidermal growth factor receptor tyrosine kinase inhibitor, cyclin-dependent kinase inhibitor, and BRAF inhibitor. The development of novel treatment options for aggressive ACTHomas is an emerging task.

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“…The main clinical presentations of neonates are pressure symptoms due to the large tumor and signs and symptoms of Cushing's disease, with high mortality [74]. A recent screening for DICER1 variants in a large cohort of Cushing's disease patients demonstrated that DICER1 gene variants may contribute to the pathogenesis of nonsyndromic corticotropinomas [75].…”

Section: Prkar1amentioning

confidence: 99%

Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

Spada¹,

Mantovani²,

Treppiedi³

et al. 2021

Neuroendocrinology

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Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

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Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Cited by 9 publications

References 42 publications

Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas

Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas

Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach

Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

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