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Transcriptomic effects of medical treatment on gene expression of growth hormone secreting pituitary neruoendocrine tumour biology

ABSTRACT: Pituitary neuroendocrine tumours (PitNET) are rare neoplasms of the pituitary gland that can overproduce pituitary hormones or cause headaches and visual impairment due to mass effect. Growth hormone overproducing somatotroph PitNETs cause acromegaly leading to wide range of connective tissue, metabolic and oncologic disorders. The medical treamment of acromegaly is somatostin analogues (SSA) in specific cases combined with dopamine agnoists (DA), but almost half of patients excert SSA resistence and potential causes of this is unknown. The aim of this study was to characterize transcriptomic patterns of somatotroph PitNETs specifically assessing impact of SSA treatment effects. We investigated gene expession on several levels and functional models of GH PitNETs - tumour tissue of patients with and without SSA preoperative treamtment, tumour derived pituisphere model and classically used GH3 cell line treated with SSA.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE200175 | GEO | 2022/04/08

REPOSITORIES: GEO

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Multilineage pituitary neuroendocrine tumors with PIT1/SF1 co-expression

Project description:Pituitary neuroendocrine tumors (PitNET)/adenomas are classified according to cell lineage, which requires immunohistochemistry for the transcription factors (TFs) PIT1, SF1, and TPIT. Co-expression of PIT1/SF1 was previously reported in PitNETs, which otherwise correspond to the somatotroph lineage. However, little is known about the clinicopathological features of these tumors. We compiled an in-house case series of 100 tumors, previously diagnosed as densely or sparsely granulated somatotroph PitNETs. Following TF staining, histopathological features associated with PIT1/SF1-coexpression were assessed. Global DNA methylation profiling was conducted on 31 of 100 in-house samples and integrated with publicly available sample data. The majority (74%, 52/70) of our densely granulated somatotroph PitNETs (DGST) unequivocally co-expressed PIT1 and SF1 (DGST-PIT1/SF1). None of our SGST (0%, 0/30) stained positive for SF1 (SGST-PIT1). Integrated molecular analyses including publicly available sample data confirmed that DGST-PIT1/SF1, DGST-PIT1 and SGST-PIT1 represent distinct tumour subtypes. In summary, we spotlight that a substantial proportion of previously diagnosed densely granulated somatotroph PitNET co-express PIT1 and SF1 and exhibit clinical, histopathological, and molecular distinctness from other pure PIT1-lineage somatotroph PitNET.

2024-01-24 | GSE246645 | GEO

Medication for acromegaly reduces expression of MUC16, MACC1 and GRHL2 in pituitary neuroendocrine tumour tissue

Project description:Acromegaly is a disease mainly caused by pituitary neuroendocrine tumours (PitNETs) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogues (SSAs), that decrease tumour mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used, if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumour tissue from twelve patients with somatotrophinomas, with half of the patients receiving SSA/DA treatment before surgery, and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein-protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumour development promoting factors MUC16, MACC1 and GRHL2, were significantly downregulated in therapy administered PitNET tissue. Protein-protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotrophinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA, significantly downregulated several factors involved in tumourigenesis, including MUC16, MACC1 and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumour suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumour effect of drug treatment.

2020-10-28 | GSE160195 | GEO

Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients' plasma

Project description:Objective Circulating plasma miRNAs have been increasingly studied in the field of pituitary neuroendocrine tumor (PitNET) research. Our aim was to discover circulating plasma miRNAs species associated with growth hormone (GH) secreting PitNETs and assess how the plasma levels of discovered miRNA candidates are impacted by SSA therapy and whether there is a difference in their levels between GH secreting PitNETs and other PitNET types. Methods miRNA candidates were discovered using the whole miRNA sequencing approach and differential expression analysis. Selected miRNAs were then analyzed using real-time polymerase chain reaction (qPCR). Results Whole miRNA sequencing discovered a total of 19 differentially expressed miRNAs (DEMs) in GH secreting PitNET patients' plasma 24 hours after surgery and 19 DEMs between GH secreting PitNET patients’ plasma and non-functioning (NF) PitNET patients’ plasma. Seven miRNAs were selected for further testing of which miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p showed a significant downregulation in plasma after 1 month of SSA treatment. miR-181a-5p and mir-625-5p were also found to be significantly downregulated in plasma of GH secreting PitNET patients vs. NF PitNET patients. Conclusions Our study suggests that expression of plasma miRNAs miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p in GH secreting PitNETs is affected by SSA treatment. Additionally, miR-625-5p and miR-181a-5p can distinguish GH secreting PitNETs from other PitNET types warranting further research on these miRNAs for treatment efficacy.

2022-02-16 | GSE196647 | GEO

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2022-12-01 | E-MTAB-11889 | biostudies-arrayexpress

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| EGAS00001003642 | EGA

Transcriptomic Profiling of Lactotroph Pituitary Neuroendocrine Tumors via RNA Sequencing and Ingenuity Pathway Analysis

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2024-04-26 | GSE240781 | GEO

Differential Gene Expression and Pathway Analysis in Growth Hormone-Secreting Pituitary Tumors According to Granulation Pattern

Project description:This study investigated differential gene expression between granulation patterns in growth hormone (GH)-secreting pituitary tumors, aiming to elucidate novel transcriptomes that explain clinical variances in patients with acromegaly. Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enrichment of neuronal development and acute inflammatory response pathways, along with a significant enhancement of JAK–STAT, phosphatidylinositol 3-kinase, and MAPK signaling. The results suggest that granulation-specific gene expression may underpin diverse clinical presentations in acromegaly, highlighting the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK–STAT signaling in SGST.

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Project description:Secretion of growth hormone by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is the most common cause of acromegaly.Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Three subtypes of the tumors were identified. Subtype 1 tumors are densely granulated tumors without GNAS mutation characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation pattern at gene body and promoter methylation. Subtype 1 has generally lower methylation level at 5’ gene regulatory regions and CpG islands as compared to other tumor clusters. Subtype 2 are densely granulated PiNETs with common GNAS-mutations while Subtype 3 are mainly sparsely granulated tumors. Methylation/expression analysis indicate that the levels of ~50% genes differentially expressed genes between tumor subtypes that are located at in differentially methylated regions are DNA methylation dependent. These DNA methylation-controlled genes include CDKN1B, CCND2, EBF3, CDH4, CDH12 MGMT, STAT5A, PLXND1, PTPRE and MMP16 as wells as genes encoding ion channels and semaphorins. Results of DNA methylation profiling confirms three molecular subtypes of somatotroph PitNETs that differ in both gene expression and methylation pattern. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated to specific methylation at both genes.

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