26 results on '"Kunicki J"'
Search Results
2. Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors.
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Pękul M, Szczepaniak M, Kober P, Rusetska N, Mossakowska BJ, Baluszek S, Kowalik A, Maksymowicz M, Zieliński G, Kunicki J, Witek P, and Bujko M
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- Humans, Female, Corticotrophs metabolism, Proto-Oncogene Proteins B-raf genetics, Endopeptidases genetics, Mutation, Deubiquitinating Enzymes genetics, Deubiquitinating Enzymes metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism, ACTH-Secreting Pituitary Adenoma metabolism, Pituitary ACTH Hypersecretion metabolism, Adenoma genetics
- Abstract
Introduction: Corticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing's disease (CD), however, some remain clinically silent. Recurrent USP8 , USP48 , BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs., Methods: Study included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8 , USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry., Results: USP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size >10mm including 3 invasive ones. They were found in Crooke's cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency., Conclusions: We confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pękul, Szczepaniak, Kober, Rusetska, Mossakowska, Baluszek, Kowalik, Maksymowicz, Zieliński, Kunicki, Witek and Bujko.)
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- 2024
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3. A systematic review on idiopathic intracranial hypertension comorbid with polycystic ovarian syndrome and its consequences.
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Rzewuska N, Kunicki J, Pieniak K, Laskus P, Zabielska B, Smolarczyk R, and Kunicki M
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- Female, Humans, Comorbidity, Obesity complications, Obesity epidemiology, Systematic Reviews as Topic, Polycystic Ovary Syndrome complications, Polycystic Ovary Syndrome epidemiology, Polycystic Ovary Syndrome diagnosis, Pseudotumor Cerebri complications, Pseudotumor Cerebri epidemiology
- Abstract
Background: A few publications have examined the frequency and medical implications of individuals with idiopathic intracranial hypertension (IIH) and polycystic ovarian syndrome (PCOS), but the findings have been inconclusive. IIH and PCOS both mainly affect obese women of reproductive age and have an impact on women's health at various levels. The aim of this systematic review was to compare the prevalence and association between comorbid IIH and PCOS, and their effect on such aspects as metabolism, abnormalities in hormone levels, and reproduction., Methods: The criterion for inclusion was a research study of patients suffering from both syndromes. We excluded review articles, case reports, and papers with an inappropriate study design, patient population or outcomes. Electronic databases PubMed, Scopus, Web of Science and gray literature were searched to retrieve studies published from inception to June 10, 2023. The risk of bias assessment was conducted utilizing Covidence software and by discussion between co-authors., Results: After applying our inclusion/exclusion criteria, we consolidated the initial pool to a final selection of 9 articles, and 2185 patients with comorbidity of these two conditions. The prevalence of PCOS among patients with IIH was observed, with incidence rates ranging from 15.5% to 57%, which is up to 8 times greater, than the 4-10% prevalence of PCOS in the general population. These data may be valuable in clinical practice for both neurologists and gynecologists., Discussion: PCOS associated with obesity facilitates concurrence of IIH. The diagnosis of concurrence of IIH and PCOS may have significant clinical implications for patients due to the accompanying hormonal disorders, obesity-related consequences, and fertility issues. Other No systematic review was found. We have registered the study in PROSPERO (International prospective register of systematic reviews), and the registration number is CRD42023437485., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
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- 2024
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4. DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors.
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Kober P, Rymuza J, Baluszek S, Maksymowicz M, Nyc A, Mossakowska BJ, Zieliński G, Kunicki J, and Bujko M
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- Humans, DNA Methylation, Transcription Factors genetics, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Somatotrophs metabolism, Growth Hormone-Secreting Pituitary Adenoma genetics, Growth Hormone-Secreting Pituitary Adenoma pathology, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, Adenoma metabolism
- Abstract
Introduction: Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression., Methods: Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression., Results: Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5' gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins., Conclusion: DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes., (© 2023 S. Karger AG, Basel.)
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- 2024
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5. Pathologic Characteristics of Somatotroph Pituitary Tumors-An Observational Single-Center Study.
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Tomasik A, Stelmachowska-Banaś M, Maksymowicz M, Czajka-Oraniec I, Raczkiewicz D, Zieliński G, Kunicki J, and Zgliczyński W
- Abstract
The pathologic evaluation of a tumor tissue is an essential part of an acromegaly patient's assessment. This study aimed to analyze the pathologic characteristics of pituitary tumors in patients with acromegaly. The demographic data, in addition to the hormonal, imaging, and pathologic results of 120 patients with acromegaly after pituitary surgery, were extracted from the Polish Acromegaly Registry. We compared sparsely and densely granulated tumors, GH(+), mixed GH(+)/PRL(+) and plurihormonal tumors, α-subunit-positive and α-subunit-negative tumors, and tumors of various Ki-67 indices in terms of the abovementioned features. Sparsely granulated tumors were more frequent in women than in men ( p = 0.001) and in younger patients ( p = 0.011), and they were larger ( p < 0.001) compared to densely granulated tumors. Tumors with positive α-subunit were smaller ( p = 0.013), showed extrasellar extension less often ( p = 0.039), and were more often densely granulated ( p < 0.001) compared to α-subunit-negative tumors. Patients with a higher Ki-67 index were younger ( p < 0.001) and more often diagnosed with genetic syndromes ( p = 0.02); they had higher GH concentrations ( p = 0.007), larger tumors ( p = 0.006), and cavernous sinus invasions more frequently ( p = 0.022). Conclusions: The pathologic characteristics of somatotroph pituitary tumors are associated with patient's age, sex, hormonal results, tumor size, and the degree of extrasellar expansion.
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- 2023
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6. DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment.
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Baluszek S, Kober P, Rusetska N, Wągrodzki M, Mandat T, Kunicki J, and Bujko M
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- Humans, CpG Islands, Gene Expression Profiling, Sequence Analysis, RNA, Tumor Microenvironment, DNA Methylation, Chordoma genetics
- Abstract
Chordomas are rare tumors of notochord remnants, occurring mainly in the sacrum and skull base. Despite of their unusually slow growth, chordomas are highly invasive and the involvement of adjacent critical structures causes treatment challenges. Due to the low incidence, the molecular pathogenesis of this entity remains largely unknown. This study aimed to investigate DNA methylation abnormalities and their impact on gene expression profiles in skull base chordomas. 32 tumor and 4 normal nucleus pulposus samples were subjected to DNA methylation and gene expression profiling with methylation microarrays and RNA sequencing. Genome-wide DNA methylation analysis revealed two distinct clusters for chordoma (termed subtypes C and I) with different patterns of aberrant DNA methylation. C Chordomas were characterized by general hypomethylation with hypermethylation of CpG islands, while I chordomas were generally hypermethylated. These differences were reflected by distinct distribution of differentially methylated probes (DMPs). Differentially methylated regions (DMRs) were identified, indicating aberrant methylation in known tumor-related genes in booth chordoma subtypes and regions encoding small RNAs in subtype C chordomas. Correlation between methylation and expression was observed in a minority of genes. Upregulation of TBXT in chordomas appeared to be related to lower methylation of tumor-specific DMR in gene promoter. Gene expression-based clusters of tumor samples did not overlap with DNA methylation-based subtypes. Nevertheless, they differ in transcriptomic profile that shows immune infiltration in I chordomas and up-regulation of cell cycle in C chordomas. Immune enrichment in chordomas I was confirmed with 3 independent deconvolution methods and immunohistochemistry. Copy number analysis showed higher chromosomal instability in C chordomas. Nine out of eight had deletion of CDKN2A/B loci and downregulation of genes encoded in related chromosomal band. No significant difference in patients' survival was observed between tumor subtypes, however, shorter survival was observed in patients with higher number of copy number alterations., (© 2023. The Author(s).)
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- 2023
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7. The expression of glucocorticoid and mineralocorticoid receptors in pituitary tumors causing Cushing's disease and silent corticotroph tumors.
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Kober P, Rusetska N, Mossakowska BJ, Maksymowicz M, Pękul M, Zieliński G, Styk A, Kunicki J, Działach Ł, Witek P, and Bujko M
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- Humans, Glucocorticoids metabolism, Corticotrophs metabolism, Hydrocortisone, Receptors, Mineralocorticoid genetics, Hypothalamo-Hypophyseal System metabolism, Adrenocorticotropic Hormone metabolism, Pituitary-Adrenal System metabolism, Pituitary Neoplasms complications, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism, Pituitary ACTH Hypersecretion surgery, Adenoma complications, Adenoma genetics, Adenoma metabolism
- Abstract
Objective: Pituitary neuroendocrine corticotroph tumors commonly cause Cushing's disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors., Methods: Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry., Results: Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8 -mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors., Conclusions: Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kober, Rusetska, Mossakowska, Maksymowicz, Pękul, Zieliński, Styk, Kunicki, Działach, Witek and Bujko.)
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- 2023
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8. A Rare Case of a Primary Leiomyoma of the Clivus in an Immunocompetent Patient and a Review of the Literature Regarding Clival Lesions.
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Kunicki J, Rzewuska N, Kunicki M, and Wiśniewski P
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Leiomyomas are common lesions that are usually located in the genitourinary and gastrointestinal tracts. Primary leiomyomas at the skull base are uncommon. They are composed of well-differentiated smooth muscle cells without cellular atypia. The diagnosis of a leiomyoma has to be confirmed by immunohistochemistry. The tumor tissue is immunoreactive for SMA, S100 and cytokeratin. Leiomyomas mainly occur in immunocompromised patients. Most tumor tissues are positive for EBV. The presented case is that of a 56-year-old immunocompetent woman with a tumor on the clivus. The radiological images suggested chordoma or fibrous dysplasia. Transnasal transsphenoidal surgery was performed. The tumor tissue consisted of well-differentiated smooth muscle cells with elongated nuclei. Immunohistochemistry revealed a positive reaction for desmin, SMA and h-Caldesmon and a negative reaction for S100, beta-catenin, PGR and Ki67. The leiomyoma diagnosis was subsequently established. To the best of our knowledge, the case of a primary leiomyoma on the clivus of an immunocompetent patient is the first to be described. We also extensively reviewed the literature on the immunohistopathological and radiological differential diagnosis of clival lesions.
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- 2022
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9. Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly.
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Rymuza J, Kober P, Rusetska N, Mossakowska BJ, Maksymowicz M, Nyc A, Baluszek S, Zieliński G, Kunicki J, and Bujko M
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- Humans, Transcriptome genetics, Growth Hormone metabolism, Gene Expression Profiling, Neuroendocrine Tumors complications, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Adenoma genetics, Pituitary Neoplasms genetics, Acromegaly genetics, Acromegaly pathology
- Abstract
Acromegaly results from growth hormone hypersecretion, predominantly caused by a somatotroph pituitary neuroendocrine tumor (PitNET). Acromegaly-causing tumors are histologically diverse. Our aim was to determine transcriptomic profiles of various somatotroph PitNETs and to evaluate clinical implication of differential gene expression. A total of 48 tumors were subjected to RNA sequencing, while expression of selected genes was assessed in 134 tumors with qRT-PCR. Whole-transcriptome analysis revealed three transcriptomic groups of somatotroph PitNETs. They differ in expression of numerous genes including those involved in growth hormone secretion and known prognostic genes. Transcriptomic subgroups can be distinguished by determining the expression of marker genes. Analysis of the entire cohort of patients confirmed differences between molecular subtypes of tumors. Transcriptomic group 1 includes ~20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors that co-express GIPR and NR5A1 (SF-1). SF-1 expression was verified with immunohistochemistry. Transcriptomic group 2 tumors are the most common (46%) and include mainly GNAS -mutated, densely granulated somatotroph and mixed PitNETs. They have a smaller size and express favorable prognosis-related genes. Transcriptomic group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing ~35% of acromegaly. Ghrelin signaling is implicated in their pathogenesis. They have an unfavorable gene expression profile and higher invasive growth rate.
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- 2022
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10. The Expression of Cell Cycle-Related Genes in USP8 -Mutated Corticotroph Neuroendocrine Pituitary Tumors and Their Possible Role in Cell Cycle-Targeting Treatment.
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Mossakowska BJ, Rusetska N, Konopinski R, Kober P, Maksymowicz M, Pekul M, Zieliński G, Styk A, Kunicki J, and Bujko M
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Protein deubiquitinases USP8 and USP48 are known driver genes in corticotroph pituitary neuroendocrine tumors (PitNETs). USP8 mutations have pleiotropic effects that include notable changes in genes' expression. Genes involved in cell cycle regulation were found differentially expressed in mutated and wild-type tumors. This study aimed to verify difference in the expression level of selected cell cycle-related genes and investigate their potential role in response to cell cycle inhibitors. Analysis of 70 corticotroph PitNETs showed that USP8 -mutated tumors have lower CDKN1B , CDK6 , CCND2 and higher CDC25A expression. USP48 -mutated tumors have lower CDKN1B and CCND1 expression. A lower p27 protein level in mutated than in wild-type tumors was confirmed that may potentially influence the response to small molecule inhibitors targeting the cell cycle. We looked for the role of USP8 mutations or a changed p27 level in the response to palbociclib, flavopiridol and roscovitine in vitro using murine corticotroph AtT-20/D16v-F2 cells. The cells were sensitive to each agent and treatment influenced the expression of genes involved in cell cycle regulation. Overexpression of mutated Usp8 in the cells did not affect the expression of p27 nor the response to the inhibitors. Downregulating or upregulating p27 expression in AtT-20/D16v-F2 cells also did not affect treatment response.
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- 2022
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11. Clinical, hormonal and pathomorphological markers of somatotroph pituitary neuroendocrine tumors predicting the treatment outcome in acromegaly.
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Tomasik A, Stelmachowska-Banaś M, Maksymowicz M, Czajka-Oraniec I, Raczkiewicz D, Zieliński G, Kunicki J, and Zgliczyński W
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- Humans, Insulin-Like Growth Factor I metabolism, Ki-67 Antigen, Male, Receptors, Somatostatin therapeutic use, Retrospective Studies, Treatment Outcome, Acromegaly diagnosis, Acromegaly drug therapy, Acromegaly surgery, Neuroendocrine Tumors, Pituitary Neoplasms drug therapy, Pituitary Neoplasms pathology, Somatotrophs chemistry, Somatotrophs metabolism, Somatotrophs pathology
- Abstract
Background: Transsphenoidal adenomectomy (TSS) of somatotroph pituitary neuroendocrine tumor (PitNET) is the first-line treatment of acromegaly. Pharmacological treatment is recommended if surgery is contraindicated or did not lead to disease remission. The choice of treatment best fitting each patient should be based on thorough investigation of patients' characteristics. The current analysis attempts to create a tool for personalized treatment planning., Aim: This study aimed to assess whether clinical, biochemical, imaging and pathological characteristics can predict surgical remission and response to first-generation somatostatin receptor ligands (SRLs) and pasireotide-LAR in acromegaly., Patients and Methods: A retrospective study of 153 acromegaly patients, treated in the Department of Endocrinology in Bielanski Hospital in Warsaw, Poland was performed. Data on demographics, hormonal and imaging results, pathological evaluation, and treatment outcome was extracted from the Polish Acromegaly Registry collecting information from 11 endocrinology centers in Poland and analyzed., Results: Patients with surgical remission had lower GH and IGF-1 concentrations at diagnosis (median GH 5.5 µg/L [IQR: 3.1-16.0] vs . 19.9 µg/L [IQR: 9.8-42.4], p=<0.001 and mean IGF-1 3.1xULN ± SD=1.2 vs. 3.7xULN ± SD=1.2, p=0.007, respectively) and smaller tumors (median 12.5mm [IQR: 9-19] vs. 23mm [IQR: 18-30], p<0.001). These tumors were more often densely granulated (DG) (73.2% vs. 40.0%, p=0.001) with positive staining for alpha-subunit (α-SU) (58.3% vs. 35.5%, p=0.021) and lower Ki-67 index (p=0.002). Patients responding well to SRLs were more often male (55.6% vs 44.4%, p=0.026), presented lower GH concentration (median GH 17.2 µg/L [IQR: 6.2-29.0] vs. 23.8 µg/L [IQR: 11.2-49.5], p=0.048) and had more often DG tumors (63.0% vs. 14.3%, p<0.001). No significant differences between good and poor-response to pasireotide-LAR groups were found. In multivariate logistic regression analysis fasting GH concentration <8.63 µg/L, maximal tumor diameter <15.5mm, normoprolactinemia and DG tumor turned out to be independent predictors of surgical remission (OR=0.92, p=0.026; OR=0.87, p=0.069, OR=3.86, p=0.096 and OR=3.05, p=0.181, respectively). Fasting GH concentration <36.6 µg/L and DG tumor turned out to be independent predictors of good response to first-generation SRLs (OR=0.96, p=0.06 and OR=10.68, p=0.002, respectively)., Conclusions: Younger age at diagnosis, male sex, lower GH, IGF-1 and PRL concentrations, smaller tumor size at diagnosis as well as positive α-SU staining, lower Ki-67 index and DG tumors predicted better treatment outcome in acromegaly patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tomasik, Stelmachowska-Banaś, Maksymowicz, Czajka-Oraniec, Raczkiewicz, Zieliński, Kunicki and Zgliczyński.)
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- 2022
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12. Giant cell tumor of the sella as a rare cause of hyperprolactinemia.
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Kunicki J, Rzewuska N, Kunicki M, Rogala P, and Wągrodzki M
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- Humans, Giant Cell Tumors complications, Hyperprolactinemia complications
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- 2022
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13. Difference in miRNA Expression in Functioning and Silent Corticotroph Pituitary Adenomas Indicates the Role of miRNA in the Regulation of Corticosteroid Receptors.
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Mossakowska BJ, Kober P, Rusetska N, Boresowicz J, Maksymowicz M, Pękul M, Zieliński G, Styk A, Kunicki J, Mandat T, and Bujko M
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- Corticotrophs metabolism, Humans, Receptors, Glucocorticoid metabolism, ACTH-Secreting Pituitary Adenoma genetics, Adenoma metabolism, MicroRNAs genetics, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism
- Abstract
Corticotroph pituitary adenomas commonly cause Cushing's disease (CD), but some of them are clinically silent. The reason why they do not cause endocrinological symptoms remains unclear. We used data from small RNA sequencing in adenomas causing CD ( n = 28) and silent ones ( n = 20) to explore the role of miRNA in hormone secretion and clinical status of the tumors. By comparing miRNA profiles, we identified 19 miRNAs differentially expressed in clinically functioning and silent corticotroph adenomas. The analysis of their putative target genes indicates a role of miRNAs in regulation of the corticosteroid receptors expression. Adenomas causing CD have higher expression of hsa-miR-124-3p and hsa-miR-135-5p and lower expression of their target genes NR3C1 and NR3C2 . The role of hsa-miR-124-3p in the regulation of NR3C1 was further validated in vitro using AtT-20/D16v-F2 cells. The cells transfected with miR-124-3p mimics showed lower levels of glucocorticoid receptor expression than control cells while the interaction between miR-124-3p and NR3C1 3' UTR was confirmed using luciferase reporter assay. The results indicate a relatively small difference in miRNA expression between clinically functioning and silent corticotroph pituitary adenomas. High expression of hsa-miR-124-3p in adenomas causing CD plays a role in the regulation of glucocorticoid receptor level and probably in reducing the effect of negative feedback mediated by corticosteroids.
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- 2022
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14. Metastasis of breast adenocarcinoma to pituitary adenoma.
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Kunicki J, Rzewuska N, Maksymowicz M, Matyja E, and Grajkowska W
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- Female, Humans, Adenocarcinoma, Adenoma diagnostic imaging, Breast Neoplasms, Pituitary Neoplasms diagnostic imaging
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- 2021
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15. Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.
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Casar-Borota O, Boldt HB, Engström BE, Andersen MS, Baussart B, Bengtsson D, Berinder K, Ekman B, Feldt-Rasmussen U, Höybye C, Jørgensen JOL, Kolnes AJ, Korbonits M, Rasmussen ÅK, Lindsay JR, Loughrey PB, Maiter D, Manojlovic-Gacic E, Pahnke J, Poliani PL, Popovic V, Ragnarsson O, Schalin-Jäntti C, Scheie D, Tóth M, Villa C, Wirenfeldt M, Kunicki J, and Burman P
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- ACTH-Secreting Pituitary Adenoma epidemiology, ACTH-Secreting Pituitary Adenoma pathology, Adenoma epidemiology, Adenoma pathology, Adolescent, Adult, Aged, Carcinoma epidemiology, Carcinoma pathology, Cohort Studies, Corticotrophs metabolism, Corticotrophs pathology, Europe epidemiology, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Neoplasm Invasiveness genetics, Pituitary Neoplasms epidemiology, Pituitary Neoplasms pathology, Young Adult, ACTH-Secreting Pituitary Adenoma genetics, Adenoma genetics, Carcinoma genetics, Pituitary Neoplasms genetics, X-linked Nuclear Protein genetics
- Abstract
Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors., Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs., Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored., Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs., Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2021
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16. Invasive and Noninvasive Nonfunctioning Gonadotroph Pituitary Tumors Differ in DNA Methylation Level of LINE-1 Repetitive Elements.
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Rusetska N, Kober P, Król SK, Boresowicz J, Maksymowicz M, Kunicki J, Bonicki W, and Bujko M
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Purpose: Epigenetic dysregulation plays a role in pituitary tumor pathogenesis. Some differences in DNA methylation were observed between invasive and noninvasive nonfunctioning gonadotroph tumors. This study sought to determine the role of DNA methylation changes in repetitive LINE-1 elements in nonfunctioning gonadotroph pituitary tumors., Methods: We investigated LINE-1 methylation levels in 80 tumors and normal pituitary glands with bisulfite-pyrosequencing. Expression of two LINE-1 open reading frames ( L1-ORF1 and L1-ORF2 ) was analyzed with qRT- PCR in tumor samples and mouse gonadotroph pituitary cells treated with DNA methyltransferase inhibitor. Immunohistochemical staining against L1-ORF1p was also performed in normal pituitary glands and tumors., Results: Hypomethylation of LINE-1 was observed in pituitary tumors. Tumors characterized by invasive growth revealed lower LINE-1 methylation level than noninvasive ones. LINE-1 methylation correlated with overall DNA methylation assessed with HM450K arrays and negatively correlated with L1-ORF1 and L1-ORF2 expression. Treatment of αT3-1 gonadotroph cells with 5-Azacytidine clearly increased the level of L1-ORF1 and L1-ORF2 mRNA; however, its effect on LβT2 cells was less pronounced. Immunoreactivity against L1-ORF1p was higher in tumors than normal tissue. No difference in L1-ORF1p expression was observed in invasive and noninvasive tumors., Conclusion: Hypomethylation of LINE-1 is related to invasive growth and influences transcriptional activity of transposable elements.
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- 2021
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17. Differential microRNA Expression in USP8 -Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes.
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Bujko M, Kober P, Boresowicz J, Rusetska N, Zeber-Lubecka N, Paziewska A, Pekul M, Zielinski G, Styk A, Kunicki J, Ostrowski J, Siedlecki JA, and Maksymowicz M
- Abstract
Background: USP8 mutations are the most common driver changes in corticotroph pituitary tumors. They have direct effect on cells' proteome through disturbance of ubiquitination process and also influence gene expression. The aim of this study was to compare microRNA profiles in USP8 -mutated and wild-type tumors and determine the probable role of differential microRNA expression by integrative microRNA and mRNA analysis., Methods: Patients with Cushing's disease ( n = 28) and silent corticotroph tumors ( n = 20) were included. USP8 mutations were identified with Sanger sequencing. MicroRNA and gene expression was determined with next-generation sequencing., Results: USP8 -mutated patients with Cushing's disease showed higher rate of clinical remission and trend towards lower tumor volume than wild-type patients. Comparison of microRNA profiles of USP8 -mutated and wild-type tumors revealed 68 differentially expressed microRNAs. Their target genes were determined by in silico prediction and microRNA/mRNA correlation analysis. GeneSet Enrichment analysis of putative targets showed that the most significantly overrepresented genes are involved in protein ubiquitination-related processes. Only few microRNAs influence the expression of genes differentially expressed between USP8 -mutated and wild-type tumors., Conclusions: Differences in microRNA expression in corticotropinomas stratified according to USP8 status reflect disturbed ubiquitination processes, but do not correspond to differences in gene expression between these tumors.
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- 2021
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18. The Search of miRNA Related to Invasive Growth of Nonfunctioning Gonadotropic Pituitary Tumors.
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Boresowicz J, Kober P, Rusetska N, Maksymowicz M, Paziewska A, Dąbrowska M, Zeber-Lubecka N, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Bujko M
- Abstract
Purpose: Nonfunctioning gonadotropic pituitary neuroendocrine tumors (PitNETs) are among the most frequent neoplasms of pituitary gland. Although PitNETs are commonly considered benign, a notable part of patients suffer from tumor recurrence after treatment. Invasive growth of pituitary tumor is among the most important prognostic factors. Since molecular features of invasiveness are of potential clinical usefulness, this study was aimed to verify whether invasive and noninvasive nonfunctioning gonadotropic PitNETs differ in the miRNA expression profile and whether the differences could provide a possible molecular classifier., Methods: miRNA profiles were determined in 20 patients (11 invasive and 9 noninvasive tumors) using next-generation sequencing. The expression of selected miRNAs was assessed in the independent cohort of 80 patients with qRT-PCR., Results: When miRNA profiles of invasive and noninvasive tumors were compared, 29 miRNAs were found differentially expressed. Hsa-miR-184, hsa-miR-181a-2-3p, hsa-miR-93-3p, hsa-miR-574-5p, hsa-miR-185-5p, and hsa-miR-3200-5p showed a potential clinical value according to ROC curve analysis. Unfortunately, differential expression of only hsa-miR-185-5p was confirmed in the validation cohort, with AUG at 0.654., Conclusion: Differences in miRNAs expression profiles in invasive and noninvasive gonadotropic PitNETs are slight and the level of miRNA expression seems not to be applicable as useful classifier of tumor invasiveness., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Joanna Boresowicz et al.)
- Published
- 2020
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19. DNA Methylation Influences miRNA Expression in Gonadotroph Pituitary Tumors.
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Boresowicz J, Kober P, Rusetska N, Maksymowicz M, Paziewska A, Dąbrowska M, Zeber-Lubecka N, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Bujko M
- Abstract
microRNAs are involved in pathogenesis of cancer. DNA methylation plays a role in transcription of miRNA-encoding genes and may contribute to changed miRNA expression in tumors. This issue was not investigated in pituitary neuroendocrine tumors (PitNETs) previously. DNA methylation patterns, assessed with HumanMethylation450K arrays in 34 PitNETs and five normal pituitaries, were used to determine differentially methylated CpGs located at miRNA genes. It showed aberrant methylation in regions encoding for 131 miRNAs. DNA methylation data and matched miRNA expression profiles, determined with next-generation sequencing (NGS) of small RNAs, were correlated in 15 PitNETs. This showed relationship between methylation and expression levels for 12 miRNAs. DNA methylation and expression levels of three of them ( MIR145 , MIR21 , and MIR184 ) were determined in the independent group of 80 tumors with pyrosequencing and qRT-PCR and results confirmed both aberrant methylation in PitNETs and correlation between methylation and expression. Additionally, in silico target prediction was combined with analysis of established miRNA profiles and matched mRNA expression pattern, assessed with amplicon-based NGS to indicate putative target genes of epigenetically deregulated miRNAs. This study reveals aberrant DNA methylation in miRNA-encoding genes in gonadotroph PitNETs. Methylation changes affect expression level of miRNAs that regulate putative target genes with tumorigenesis-relevant functions.
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- 2020
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20. USP8 mutations in corticotroph adenomas determine a distinct gene expression profile irrespective of functional tumour status.
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Bujko M, Kober P, Boresowicz J, Rusetska N, Paziewska A, Dąbrowska M, Piaścik A, Pękul M, Zieliński G, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Maksymowicz M
- Subjects
- Adult, Aged, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Connexin 43 genetics, Connexin 43 metabolism, Female, GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, Humans, Immunohistochemistry, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Zinc Finger Protein Gli2 genetics, Zinc Finger Protein Gli2 metabolism, ACTH-Secreting Pituitary Adenoma genetics, ACTH-Secreting Pituitary Adenoma metabolism, Endopeptidases genetics, Endosomal Sorting Complexes Required for Transport genetics, Mutation genetics, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism, Ubiquitin Thiolesterase genetics
- Abstract
Objective: Pituitary corticotroph adenomas commonly cause Cushing's disease (CD) but part of these tumours are hormonally inactive (silent corticotroph adenomas, SCA). USP8 mutations are well-known driver mutations in corticotrophinomas. Differences in transcriptomic profiles between functioning and silent tumours or tumours with different USP8 status have not been investigated., Design and Methods: Forty-eight patients (28 CD, 20 SCA) were screened for USP8 mutations with Sanger sequencing. Twenty-four patients were included in transcriptomic profiling with Ampliseq Transcriptome Human Gene Expression Core Panel. The entire patients group was included in qRT-PCR analysis of selected genes expression. Immunohistochemistry was used for visualization of selected protein., Results: We found USP8 mutation in 15 patients with CD and 4 SCAs. USP8 mutations determine molecular profile of the tumours as showed by hierarchical clustering and identification of 1648 genes differentially expressed in USP8-mutated and USP8-wild-type tumours. Mutations affect many molecular pathways as observed in Gene Set Enrichment analysis. USP8-mutated adenomas showed higher level of POMC, CDC25A, MAPK4 but lower level of CCND2, CDK6, CDKN1B than USP8-wt tumours. Eighty-seven genes differentially expressed between CD-related adenomas and SCAs were found, including those involved in cell signalling (GLI2, DLC1, TBX2, RASSF6), cell adhesion (GJA1, CDH6), ion transport (KCNN4, KCNJ5) and GABA signalling (GABBR2, GABRD)., Conclusion: USP8 mutations occur in functioning and silent corticotrophinomas. They have pleiotropic effect, not limited to EGFR signalling, and affect expression levels of many genes involved in different pathways. Expression of GABA-related genes GABBR2, GNAL, GABARD and KCNJ5 correspond to functional status of the tumours.
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- 2019
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21. The Role of Aberrant DNA Methylation in Misregulation of Gene Expression in Gonadotroph Nonfunctioning Pituitary Tumors.
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Kober P, Boresowicz J, Rusetska N, Maksymowicz M, Paziewska A, Dąbrowska M, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Bujko M
- Abstract
Gonadotroph nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors, but the role of aberrant epigenetic regulation in their development remains poorly understood. In this study, we investigated the effect of impaired CpG methylation in NFPAs. We determined DNA methylation and transcriptomic profiles in 32 NFPAs and normal pituitary sections using methylation arrays and sequencing, respectively. Ten percent of differentially methylated CpGs were correlated with gene expression, and the affected genes are involved in a variety of tumorigenesis-related pathways. Different proportions of gene body and promoter region localization were observed in CpGs with negative and positive correlations between methylation and gene expression, and different proportions of CpGs were located in 'open sea' and 'shelf/shore' regions. The expression of ~8% of genes differentially expressed in NFPAs was related to aberrant methylation. Methylation levels of seven CpGs located in the regulatory regions of FAM163A , HIF3A and PRSS8 were determined by pyrosequencing, and gene expression was measured by qRT-PCR and immunohistochemistry in 83 independent NFPAs. The results clearly confirmed the negative correlation between methylation and gene expression for these genes. By identifying which aberrantly methylated CpGs affect gene expression in gonadotrophinomas, our data confirm the role of aberrant methylation in pathogenesis of gonadotroph NFPAs.
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- 2019
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22. DNA methylation profiling in nonfunctioning pituitary adenomas.
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Kober P, Boresowicz J, Rusetska N, Maksymowicz M, Goryca K, Kunicki J, Bonicki W, Siedlecki JA, and Bujko M
- Subjects
- Adenoma pathology, Adult, Aged, Aged, 80 and over, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Pituitary Neoplasms pathology, Promoter Regions, Genetic, Adenoma genetics, DNA Methylation genetics, Pituitary Neoplasms genetics
- Abstract
Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood. We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients. NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors., (Copyright © 2018 Elsevier B.V. All rights reserved.)
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- 2018
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23. Telomere length and TERT abnormalities in pituitary adenomas.
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Boresowicz J, Kober P, Rusetska N, Maksymowicz M, Goryca K, Kunicki J, Bonicki W, and Bujko M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, DNA Methylation, Female, Gene Dosage, Gene Expression Regulation, Neoplastic genetics, Genome-Wide Association Study, Humans, Incidence, Male, Middle Aged, Mutation, Missense genetics, RNA, Messenger biosynthesis, Young Adult, Adenoma genetics, Adenoma pathology, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, Telomerase genetics, Telomere pathology
- Abstract
Objectives: Pituitary adenomas (PAs) are among the most frequent intracranial tumors in humans. Abnormal telomerase activity and telomere lengthening are features of tumor cells. They may result from mutations in TERT promoter region, gene amplification or aberrant DNA methylation pattern. Such changes were found in variety of tumors including those of brain. Aim of the study was to evaluate the incidence of TERT abnormalities and to assess their role in telomere lengthening in PAs., Methods: Study involved 101 patients with PA including both nonfunctioning and functioning subtypes. Telomerase length as well as TERT mRNA level and gene amplification were estimated using quantitative PCR (qPCR). Promoter mutations were assessed using Sanger sequencing. The results from genome-wide DNA methylation profiling with HumanMethylation 450K (Illumina) were used for the analysis of TERT locus., Results: Variable telomere length was observed in patients, however no relationship with clinicopathological features was found. We observed a missense variant in TERT promoter in one patient only whereas increased TERT copy number were identified in 6 patients (5.6%). However no relationship between these results and telomere length or TERT expression was found. DNA methylation at TERT locus was not found to be changed when adenoma samples and normal tissue sections were compared., Conclusion: The results indicate that telomerase abnormalities do not play a role in pathogenesis of pituitary tumors.
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- 2018
24. AB thymoma with atypical type A component with delayed multiple lung and brain metastases.
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Grajkowska W, Matyja E, Kunicki J, Szymanska S, Marx A, Weis CA, Langfort R, and Szolkowska M
- Abstract
An atypical type A thymoma is a newly added entity to the last World Health Organization (WHO) histological classification [2015] of uncertain prognosis. The conventional type A and AB thymomas are usually locally aggressive neoplasms that rarely metastasize with distant metastases to the central nervous system (CNS) occurring extremely exceptionally. We present a history of a woman with a mediastinal tumor originally considered to be a Masaoka-Koga stage II "mixed thymoma with well-differentiated thymic carcinoma component" according to the historic Müller-Hermelink nomenclature. By applying the criteria of the new WHO classification the tumor should be reclassified as an AB thymoma with an atypical A component. The patient developed metastases to the lung and brain 10 and 15 years after the original diagnosis, respectively. All metastases morphologically corresponded to an atypical A component of primary thymoma. Molecular study revealed GTF2I mutations in the primary and one of the metastatic tumors. To our knowledge, this is the first description of a GTF2I mutation in AB thymoma with atypical A component and its metastases. The presented case highlights the necessity of an accurate microscopic search for atypical areas in A or AB thymomas because of their potentially negative impact on prognosis., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
- Published
- 2017
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25. Ganglion cell tumours in the sella turcica in close morphological connection with pituitary adenomas.
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Matyja E, Maksymowicz M, Grajkowska W, Zieliński G, Kunicki J, Bonicki W, Witek P, and Naganska E
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- Adult, Female, Humans, Male, Middle Aged, Adenoma pathology, Ganglioneuroma pathology, Neoplasms, Multiple Primary pathology, Pituitary Neoplasms pathology, Sella Turcica pathology
- Abstract
Ganglion cell tumours in the sellar region are uncommon. They are usually associated with pituitary adenomas, while isolated ganglion cell neoplasms are extremely rare. We report the clinicopathological studies of five cases diagnosed as ganglion cell tumours located in the intrasellar region: four mixed/collision tumours composed of gangliocytoma and pituitary adenoma, and one isolated ganglioglioma unrelated to adenoma. Clinically, two patients presented with acromegaly, while three others were initially diagnosed as non-functioning adenomas. In four cases, the histopathological examination of surgical specimens revealed intermixed lesions composed of pituitary adenoma and ganglion cell elements. The adenomas appeared to secrete growth hormone. Electron microscopy enabled identification of the sparsely granulated somatotroph cells. Neoplastic neuronal lesions were composed of mature ganglion cells, including binucleate or multinucleate cells. In all cases, boundaries between adenomatous and gangliocytic components were not clearly demarcated, and numerous gangliocytic cells were closely intermingled with adenomatous tissue. One case lacked endocrine symptoms, and no pituitary adenoma was identified in the surgically excised material; it was finally diagnosed as low-grade ganglioglioma. The etiopathogenesis of ganglion cell neoplasms in the sellar region is not clearly defined. Our study revealed that if ganglion cell neoplasms were combined with adenoma, both neoplastic components were closely related to each other, and numerous neuronal elements were strictly intermingled with adenoma cells. Such a tissue pattern indicates that these neoplastic changes, including their common respective etiopathogeneses, are closely related. The identification of both components in sellar regions may have some nosological implications.
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- 2015
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26. Microsatellite instability analysis in pituitary adenomas.
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Bujko M, Kober P, Zbijewska J, Kunicki J, and Bonicki W
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Electrophoresis, Capillary, Female, Humans, Male, Middle Aged, Pituitary Neoplasms genetics, Polymerase Chain Reaction, Young Adult, ACTH-Secreting Pituitary Adenoma genetics, Adenoma genetics, Biomarkers, Tumor genetics, Growth Hormone-Secreting Pituitary Adenoma genetics, Microsatellite Instability, Prolactinoma genetics
- Abstract
Objective: Mutator phenotypes with microsatellite instability (MSI) are observed in a subset of solid tumors including those localized in the brain. MSI arises from impaired DNA mismatch repair. It can be a potential marker of resistance to radiation and chemotherapy, as demonstrated for several cancer types. Our study aims are to investigate MSI incidence in pituitary adenomas (PA) with a currently recommended methodology., Methods: DNA was obtained from 107 patients with PA of which 83 adenomas were nonfunctioning, 13 somatotrophic, 9 lactotrophic and 2 corticotrophic. These were examined for MSI status by PCR and capillary electrophoresis using five quasimonomorphic microsatellite markers: BAT25, BAT26, NR21, NR24 and NR27; in accordance to current Bethesda guidelines., Results and Conclusion: No microsatellite instability was detected in the tumor samples thus implying the lack of any clinical usefulness of MSI testing in PA cases.
- Published
- 2015
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