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Journal of Experimental & Clinical... Jan 2022Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1), but its functional effects and underlying molecular mechanisms remain...
BACKGROUND
Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1), but its functional effects and underlying molecular mechanisms remain largely unexplored.
METHODS
Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1 mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1 were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA.
RESULTS
Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1 allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1 promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1 and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway.
CONCLUSIONS
Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1 mutation.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Line, Tumor; Discs Large Homolog 1 Protein; Disease Progression; Humans; Membrane Proteins; Mutation; Phosphoproteins; Pituitary Neoplasms; Prolactinoma; RNA Splicing; RNA Splicing Factors; Rats; Transfection
PubMed: 35039052
DOI: 10.1186/s13046-022-02245-0 -
International Journal of Molecular... Oct 2021Prolactinoma has the highest incidence rate among patients with functional pituitary tumours. Although mostly benign, there is a subgroup that can be aggressive. Some... (Review)
Review
Prolactinoma has the highest incidence rate among patients with functional pituitary tumours. Although mostly benign, there is a subgroup that can be aggressive. Some clinical, radiological and pathology features have been associated with a poor prognostic. Therefore, it can be considered as a group of heterogeneous tumours. The aim of this paper is to give an overview of the molecular pathways involved in the behaviour of prolactinoma in order to improve our approach and gain deeper insight into the better understanding of tumour development and its management. This is essential for identifying patients harbouring aggressive prolactinoma and to establish personalised therapeutics options.
Topics: Animals; Antineoplastic Agents; Dopamine Agonists; Humans; Pituitary Neoplasms; Prolactinoma; Signal Transduction
PubMed: 34681905
DOI: 10.3390/ijms222011247 -
Pituitary Feb 2020Renewed interest in transsphenoidal surgery (TSS) as a therapeutic option for prolactinomas has emerged. (Review)
Review
PURPOSE
Renewed interest in transsphenoidal surgery (TSS) as a therapeutic option for prolactinomas has emerged.
METHODS
Based on contemporary literature and own experience, the changing role of surgery for treatment of prolactinomas is discussed.
RESULTS
Today, TSS is performed by minimally invasive microscopic or endoscopic techniques. Normoprolactinemia is obtained in 71-100% of patients with microprolactinomas by TSS. Almost equal results are found in circumscribed intrasellar macroprolactinomas. In experienced hands, pituitary function is preserved in TSS. The risk of cardiac valve disease is still a concern with ergot-derived dopamine-agonists (DAs) in patients requiring long-term, high-dose dopamine-agonist (DA) treatment. Cost-utility analysis favors TSS over DA treatment. The possible negative impact of DA treatment on future surgical results is still a controversial and unsettled issue. In patients who wish to become pregnant, the advantages of microprolactinoma removal to avoid DAs and macroprolactinoma debulking to avoid symptomatic enlargement during pregnancy should be discussed with the patients. Young patients' age is an argument for surgery to circumvent the unpredictable sequelae of long-term DA treatment. Surgery should be discussed in male gender because of a higher likelihood of DA resistance and aggressive behavior of prolactinoma.
CONCLUSION
Given excellent results of TSS and concerns about medical treatment, the scale of indications for TSS as an alternative to DAs has increased. The patient's wishes concerning a chance at a cure with TSS instead of a long-term treatment with DAs has become an important and accepted indication. With DA medication and TSS, two effective treatment modalities for prolactinomas are available that can be used in a complementary fashion.
Topics: Dopamine Agonists; Female; Humans; Male; Prolactinoma; Treatment Outcome
PubMed: 31853793
DOI: 10.1007/s11102-019-01016-z -
Trends in Endocrinology and Metabolism:... Apr 2020The pituitary hormone prolactin (PRL) regulates a variety of functions beyond reproduction. The association between physiological (pregnancy) and pathological... (Review)
Review
The pituitary hormone prolactin (PRL) regulates a variety of functions beyond reproduction. The association between physiological (pregnancy) and pathological (prolactinoma) hyperprolactinemia and metabolic alterations led to the concept of this hormone being diabetogenic. However, large cohort clinical studies have recently shown that low circulating PRL levels are associated with metabolic disease and represent a risk factor for type 2 diabetes (T2D), whereas high PRL levels are beneficial. Moreover, PRL acts on the pancreas, liver, adipose tissue, and hypothalamus to maintain and promote metabolic homeostasis. By integrating basic and clinical evidence, we hypothesize that upregulation of PRL levels is a mechanism to maintain metabolic homeostasis and, thus, propose that the range of PRL levels considered physiological should be expanded to higher values.
Topics: Diabetes Mellitus, Type 2; Dopamine Agents; Female; Homeostasis; Humans; Hyperprolactinemia; Obesity; Prolactin; Prolactinoma
PubMed: 32044206
DOI: 10.1016/j.tem.2020.01.004 -
European Journal of Endocrinology Dec 2023Prolactinomas represent 46%-66% of pituitary adenomas, but the prevalence of germline mutations is largely unknown. We present here the first study focusing on...
BACKGROUND
Prolactinomas represent 46%-66% of pituitary adenomas, but the prevalence of germline mutations is largely unknown. We present here the first study focusing on hereditary predisposition to prolactinoma.
OBJECTIVE
We studied the prevalence of germline mutations in a large cohort of patients with isolated prolactinomas.
MATERIALS AND METHODS
A retrospective study was performed combining genetic and clinical data from patients referred for genetic testing of MEN1, AIP, and CDKN1B between 2003 and 2020. SF3B1 was Sanger sequenced in genetically negative patients.
RESULTS
About 506 patients with a prolactinoma were included: 80 with microprolactinoma (15.9%), 378 with macroprolactinoma (74.7%), 48 unknown; 49/506 in a familial context (9.7%). Among these, 14 (2.8%) had a (likely) pathogenic variant (LPV) in MEN1 or AIP, and none in CDKN1B. All positive patients had developed a macroprolactinoma before age 30. The prevalence of germline mutations in patients with isolated macroprolactinoma under 30 was 4% (11/258) in a sporadic context and 15% (3/20) in a familial context. Prevalence in sporadic cases younger than 18 was 15% in men (5/33) and 7% in women (4/57). No R625H SF3B1 germline mutation was identified in 264 patients with macroprolactinomas.
CONCLUSIONS
We did not identify any LPVs in patients over 30 years of age, either in a familial or in a sporadic context, and in a sporadic context in our series or the literature. Special attention should be paid to young patients and to familial context.
Topics: Male; Humans; Female; Adult; Prolactinoma; Cohort Studies; Retrospective Studies; Genetic Testing; Pituitary Neoplasms; Germ-Line Mutation
PubMed: 37956455
DOI: 10.1093/ejendo/lvad148 -
Neurosurgery Clinics of North America Oct 2019Pituitary adenomas are a rare but important central nervous system tumor in children. Because of differences in growth and development, the manifestations of pituitary... (Review)
Review
Pituitary adenomas are a rare but important central nervous system tumor in children. Because of differences in growth and development, the manifestations of pituitary adenomas in children may differ from those seen in adults. Unlike adult patients, the pediatric population more often presents with clinically secretory adenomas. Although medical management is first-line treatment of prolactinomas, transsphenoidal surgery is appropriate for most children with Cushing disease and gigantism. Although some pediatric patients present surgical challenges because of small anatomic dimensions or an incompletely developed sphenoid sinus, transsphenoidal surgery can be safely and effectively undertaken in most children, with low complication rates.
Topics: Adenoma; Child; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prolactinoma; Sphenoid Bone; Treatment Outcome
PubMed: 31471053
DOI: 10.1016/j.nec.2019.05.008 -
Neurosurgery Clinics of North America Oct 2019Pituitary adenomas are benign tumors, but still cause significant morbidity and in some cases increases in mortality. Surgical resection is not without risks, and... (Review)
Review
Pituitary adenomas are benign tumors, but still cause significant morbidity and in some cases increases in mortality. Surgical resection is not without risks, and approximately 40% of adenomas are incompletely resected. Medical therapies such as dopamine agonists, somatostatin analogues, and growth hormone antagonists are associated with numerous side effects. Understanding the molecular biology of pituitary adenomas may yield new therapeutic approaches. Additional studies are needed to help determine which genes or pathways are "drivers" of tumorigenesis and should be therapeutic targets. Further studies may also enable pituitary adenoma stratification to tailor treatment approaches.
Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Animals; DNA-Binding Proteins; Epigenesis, Genetic; Growth Hormone-Secreting Pituitary Adenoma; Humans; Pituitary Neoplasms; Prolactinoma; Signal Transduction; Viral Proteins
PubMed: 31471046
DOI: 10.1016/j.nec.2019.05.001 -
Innere Medizin (Heidelberg, Germany) Jul 2024The widespread use of diagnostic imaging has led to an increase in the incidence of pituitary tumors. The majority of incidentalomas are hormone-inactive (HI) pituitary... (Review)
Review
The widespread use of diagnostic imaging has led to an increase in the incidence of pituitary tumors. The majority of incidentalomas are hormone-inactive (HI) pituitary microadenomas. The most common clinically relevant pituitary adenomas are prolactin-secreting, followed by HI, and far less common are growth hormone (GH)-, adrenocorticotropic hormone (ACTH)- and thyroid-stimulating hormone (TSH)-secreting adenomas. Pituitary adenomas are usually benign, although aggressive growth and invasion occurs in individual cases. Very rarely, they give rise to metastases and are then termed pituitary carcinomas. All pituitary tumors require endocrine testing for pituitary hormone excess. In addition to the medical history and clinical examination, laboratory diagnostics are very important. Symptoms such as irregular menstruation, loss of libido or galactorrhea often lead to the timely diagnosis of prolactinomas, and hyperprolactinemia can easily confirm the diagnosis (considering the differential diagnoses). Diagnosis is more difficult for all other hormone-secreting pituitary adenomas (acromegaly, Cushing's disease, TSHoma), as the symptoms are often non-specific (i.e., headaches, weight gain, fatigue, joint pain). Furthermore, comorbidities such as hypertension, diabetes, and depression are such widespread diseases that pituitary adenomas are rarely considered as the underlying cause. Timely diagnosis and appropriate treatment have a significant impact on morbidity, mortality, and quality of life. Therefore, the role of primary care physicians is very important for achieving an early diagnosis. In addition, patients with pituitary adenomas should always be referred to endocrinologists to ensure optimal diagnosis as well as treatment.
Topics: Humans; Pituitary Neoplasms; Diagnosis, Differential; Adenoma; Prolactinoma
PubMed: 38869654
DOI: 10.1007/s00108-024-01729-9 -
Journal of Medical Case Reports Apr 2022Managing treatment-resistant aggressive giant prolactinoma can be challenging, as the diagnosis is often complex, and treatment beyond dopamine agonists, surgery, and...
BACKGROUND
Managing treatment-resistant aggressive giant prolactinoma can be challenging, as the diagnosis is often complex, and treatment beyond dopamine agonists, surgery, and radiotherapy is limited.
CASE PRESENTATION
A 21-year-old Malay woman first presented to our hospital at the age of 16 years with 1-year history of reduced vision and 2 years of amenorrhea. Her baseline prolactin level was 255,894 µIU/mL with secondary hypogonadism, and pituitary magnetic resonance imaging revealed a giant prolactinoma (2.8 × 3.2 × 4.2 cm) with suprasellar extension and optic chiasmal compression. She was initially treated with cabergoline, and reductions in the prolactin level and tumor mass were achieved, leading to vision improvement and resumption of normal menstruation. However, she developed recurrent tumor growth and hyperprolactinemia, causing relapse of symptoms, and she needed surgery. Eventually, despite three tumor debulking surgeries and escalation of cabergoline doses up to 1 mg/day, her tumor progressed with aggressive characteristics. Following a multidisciplinary meeting, the patient is initiated on temozolomide therapy after considering the long-term side effects of radiotherapy in her case.
CONCLUSION
This case highlights the importance of early identification of treatment-resistant prolactinoma and the need for a multidisciplinary approach in managing aggressive prolactinoma in young patients, particularly regarding timely implementation of temozolomide therapy.
Topics: Adolescent; Adult; Cabergoline; Female; Humans; Neoplasm Recurrence, Local; Pituitary Neoplasms; Prolactin; Prolactinoma; Temozolomide; Young Adult
PubMed: 35488355
DOI: 10.1186/s13256-022-03390-y