Epigenetic change in pituitary tumorigenesis.

2003 ◽  
pp. 323-330 ◽  
Author(s):  
W E Farrell ◽  
R N Clayton
Keyword(s):  
Cpg Islands ◽  
Pituitary Tumour ◽  
Histone Deacetylation ◽  
Pituitary Tumours ◽  
Kinase Gene ◽  
Expected Frequency ◽  
Cpg Dinucleotides ◽  
Pituitary Tumorigenesis ◽  
Frequent Event ◽  
Death Associated Protein Kinase

Throughout the genome CpG dinucleotides are found at one-fifth of their expected frequency and their rarity is further marked by the fact that 70% are methylated. In contrast, CpG islands (CGI), found associated with the promoters of many genes, have maintained their expected frequency of this dinucleotide, and remain unmethylated. Inappropriate methylation of CGIs is associated with histone deacetylation and gene silencing, while methylation of CpGs outside of CGIs is associated with significantly higher mutation rates. Methylation of CGIs is a frequent event in numerous tumour types including those that arise within the pituitary gland. Several studies now show highly frequent methylation of the p16 gene that is significantly associated with loss of cognate protein and that appears to be an early change in pituitary tumorigenesis. Collectively, studies show that somatotrophinomas are an infrequent target for p16 CGI methylation. However, in this pituitary tumour subtype, loss of pRb is associated with either CGI methylation or micro-deletion within the protein-pocket binding domain. As in other tumour types loss of p16 or RB1 appear to be mutually exclusive events in non-functional adenomas and somatotrophinomas respectively. Investigation of the Death Associated Protein Kinase gene shows that loss of its protein (DAPK), a pro-apoptotic molecule, in pituitary tumours is also associated with either methylation or deletion within its associated CGI. In the case of DAPK, however, these changes segregate with invasive pituitary tumours irrespective of tumour subtype. Methylation represents a positive signal that can be detected with exquisite sensitivity; in addition, this change targets multiple genes that show tumour type specificity. Taken together, the detection of DNA methylation changes, using either a panel of predefined marker-islands, or CGI arrays, provides the opportunity to generate "methylation profiles". This new knowledge will increase our understanding of tumour biology and could ultimately aid medical management in these different tumour types, including those of pituitary origin.

scholarly journals Pituitary tumours: findings from whole genome analyses

2006 ◽  
Vol 13 (3) ◽  
pp. 707-716 ◽  
Author(s):  
W E Farrell
Keyword(s):  
Animal Models ◽  
New Technologies ◽  
Pituitary Tumour ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Pituitary Tumours ◽  
Novel Genes ◽  
Human Pituitary ◽  
Genome Wide ◽  
Pituitary Tumorigenesis

Pituitary tumours are common intracranial neoplasms that cause significant morbidity through mass effects and/or the inappropriate secretion of pituitary hormones. Despite a considerable literature detailing potential pathogenic changes in these tumours, their aetiology remains largely unresolved. Recent studies have employed genome-wide profiling towards the identification of novel genes and pathways that are inappropriately expressed or regulated in this tumour type. The techniques employed vary in their complexity and interpretation; however, many of the findings from these types of studies have identified novel genes with potential and, in some cases, proven roles in pituitary tumorigenesis. These studies include comparative genomic hybridization, whole genome-wide allelotyping and methodologies for identification of novel genes associated with epigenetic silencing. In addition, differential display methodologies have been instrumental in the identification of transcripts inappropriately expressed including, pituitary tumour transforming gene, growth arrest and DNA damage-inducible protein (GADD)45γ and a maternal expressed gene 3 isoform, which in some cases have proven roles in pituitary tumorigenesis. Although few studies of whole genome transcript analysis, as determined by microarray or gene-chip technologies, are reported, these studies of human pituitary, in some cases combined with proteomics, are yielding useful data. In addition, these types of investigation have been applied to several animal models of pituitary tumorigenesis, and in these cases novel genes are highlighted as showing significant change. The identification of the initiating events responsible for the transformation of a normal pituitary cell into one with unrestrained proliferative capacity has so far eluded us. No doubt, these new technologies allowing an essentially unbiased genome-wide analysis, perhaps in combination with animal models that display a preceding hyperplasia, will allow us to identify genes critical to tumour evolution and progression.

scholarly journals PTTG--a new pituitary tumour transforming gene

1999 ◽  
Vol 162 (2) ◽  
pp. 163-166 ◽  
Author(s):  
CJ McCabe ◽  
NJ Gittoes
Keyword(s):  
Cell Transformation ◽  
Pituitary Tumour ◽  
Strongly Correlated ◽  
Pituitary Tumours ◽  
Acid Protein ◽  
Pituitary Tumorigenesis ◽  
Acute Myelogenous ◽  
Transforming Gene ◽  
Amino Acid Protein

The pathogenesis of sporadic pituitary tumours remains elusive. Recently, a new candidate gene has been described which is able to induce pituitary cell transformation, and the expression of which appears to be strongly correlated with pituitary tumorigenesis. The so-called pituitary tumour transforming gene (PTTG) encodes a 23 kDa, 202 amino acid protein, and is located on chromosome 5q33, a locus previously associated with recurrent lung cancer and acute myelogenous leukaemias. Although the precise function of PTTG protein is unknown, in vitro experiments have demonstrated that it is capable of inducing fibroblast growth factor (FGF) expression. Mutation of the two proline-rich domains of the PTTG protein has also been shown to abolish subsequent FGF induction. Furthermore, in patients with pituitary adenomas, serum FGF concentrations fall post-operatively after successful excision of the tumour.

A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: secreting versus non-secreting adenomas.

2002 ◽  
pp. 103-113 ◽  
Author(s):  
M L Jaffrain-Rea ◽  
D Di Stefano ◽  
G Minniti ◽  
V Esposito ◽  
A Bultrini ◽  
...  
Keyword(s):  
Operative Treatment ◽  
Hormone Secretion ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Labelling Index ◽  
Pituitary Tumours ◽  
Life Threatening ◽  
The Mean ◽  
Monoclonal Antibody Mib 1 ◽  
Mib 1

Pituitary tumours are usually benign neoplasia, but may have a locally aggressive or malignant evolution. This study aimed to identify factors which mostly influence their proliferative activity, in order to clarify its value for clinical and research purposes. The proliferative index was determined in a prospective series of 132 pituitary tumours as the percentage of monoclonal antibody MIB-1-immunopositive cells and referred to as the MIB-1 labelling index (LI). Its distribution was analysed according to both univariate and multivariate models. A life-threatening pituitary tumour is presented separately. The mean LI was 1.24+/-1.59%, with significant differences between clinically secreting (CS) and clinically non-secreting (CNS) adenomas. In CS adenomas (n=65), LI was highly variable and markedly influenced by pre-operative pharmacological treatment (0.80+/-1.03 vs 2.06+/-2.39% in treated vs untreated cases, P=0.009); it decreased with patient's age (P=0.025, r=0.28) and increased with tumour volume and invasiveness. The influence of pre-operative treatment and macroscopic features on LI in this group was confirmed by multivariate analysis. In CNS adenomas (n=67), LI distribution was less variable than in CS adenomas (P<0.0001), it was age-independent and correlations with tumour volume, invasiveness or recurrence did not reach significance. In a rapidly growing parasellar tumour, the mean LI was 24% at first surgery and exceeded 50% at second surgery performed 4 months later. LI should be interpreted according to hormone secretion and pre-operative treatment. Unusually high LI values deserve particular attention.

scholarly journals The pre- and postoperative illness trajectory in patients with pituitary tumours

2019 ◽  
Vol 8 (7) ◽  
pp. 878-886 ◽  
Author(s):  
Eva Jakobsson Ung ◽  
Ann-Charlotte Olofsson ◽  
Ida Björkman ◽  
Tobias Hallén ◽  
Daniel S Olsson ◽  
...  
Keyword(s):  
Postoperative Care ◽  
Care Pathway ◽  
Pituitary Surgery ◽  
Pituitary Tumour ◽  
Postoperative Recovery ◽  
Endocrine Treatment ◽  
Pituitary Tumours ◽  
Care And Support ◽  
Before And After ◽  
Operative Evaluation

Objective Experiences and need of support during surgery and start of replacement therapy in patients with pituitary tumours are highly unknown. This study aimed at exploring patient experiences during pre- and postoperative care and recovery after pituitary surgery in patients with a pituitary tumour. Methods Within a qualitative study design, 16 consecutive patients who underwent surgery for pituitary tumours were repeatedly interviewed. In total, 42 interviews were performed before and after surgery. Analysis was performed using qualitative interpretation. Results Suffering a pituitary tumour was overwhelming for many patients and struggling with existential issues was common. Patients expressed loneliness and vulnerability before and after surgery. How professionals handled information in connection with diagnosis greatly affected the patients. Other patients with the same diagnosis were experienced as the greatest support. Normalisation of bodily symptoms and relationships with others were reported during postoperative recovery. However, a fear that the tumour would return was present. Conclusions Patients with pituitary tumours need structured support, including peer support, which acknowledges physical, cognitive as well as emotional and existential concerns. Information related to diagnosis and surgery should be adapted in relation to the loneliness and the existential seriousness of the situation. Care and support for patients with pituitary tumours should preferably be organised based on continuity and an unbroken care pathway from the first pre-operative evaluation through to postoperative care and the start of a life-long endocrine treatment and tumour surveillance.

scholarly journals Demethylation of somatic and testis-specific histone H2A and H2B genes in F9 embryonal carcinoma cells

1993 ◽  
Vol 13 (9) ◽  
pp. 5538-5548
Author(s):  
Y C Choi ◽  
C B Chae
Keyword(s):  
Embryonal Carcinoma ◽  
Cpg Island ◽  
Cpg Islands ◽  
High Density ◽  
Carcinoma Cells ◽  
Embryonal Carcinoma Cells ◽  
Cpg Dinucleotides ◽  
F9 Embryonal Carcinoma Cells ◽  
Methylation Patterns

In contrast to many other genes containing a CpG island, the testis-specific H2B (TH2B) histone gene exhibits tissue-specific methylation patterns in correlation with gene activity. Characterization of the methylation patterns within a 20-kb segment containing the TH2A and TH2B genes in comparison with that in a somatic histone cluster revealed that: (i) the germ cell-specific unmethylated domain of the TH2A and TH2B genes is defined as a small region surrounding the CpG islands of the TH2A and TH2B genes and (ii) somatic histone genes are unmethylated in both liver and germ cells, like other genes containing CpG islands, whereas flanking sequences are methylated. Transfection of in vitro-methylated TH2B, somatic H2B, and mouse metallothionein I constructs into F9 embryonal carcinoma cells revealed that the CpG islands of the TH2A and TH2B genes were demethylated like those of the somatic H2A and H2B genes and the metallothionein I gene. The demethylation of those CpG islands became significantly inefficient at a high number of integrated copies and a high density of methylated CpG dinucleotides. In contrast, three sites in the somatic histone cluster, of which two sites are located in the long terminal repeat of an endogenous retrovirus-like sequence, were efficiently demethylated even at a high copy number and a high density of methylated CpG dinucleotides. These results suggest two possible mechanisms for demethylation in F9 cells and methylation of CpG islands of the TH2A and TH2B genes at the postblastula stage during embryogenesis.

scholarly journals Safety and efficacy of mini doppler in recurrent pituitary tumours

2020 ◽  
pp. 336-342
Author(s):  
Moshiur Rahman ◽  
Ezequiel Garcia-Ballestas ◽  
Luis Rafael Moscote-Salazar
Keyword(s):  
Cavernous Sinus ◽  
Surgical Excision ◽  
Pituitary Surgery ◽  
Pituitary Tumour ◽  
Csf Leak ◽  
Surgical Removal ◽  
Pituitary Tumours ◽  
Female Ratio ◽  
Cavernous Sinus Invasion ◽  
Number Of Patients

Background: Pituitary surgery is the most common surgery used to remove pituitary tumours. The use of mini doppler in surgical removal of an endonasal pituitary tumour has shown good short-term clinical outcomes and few complications in patients. Cavernous sinus invasion limits the surgical excision and still a challenge of gross total resection.   Objective: The main objective of this study is to evaluate the outcome of surgical removal of an endonasal pituitary tumour using mini doppler.    Method: A total of 12 patients were studied retrospectively from 2012 to 2018 in a single institution (Private hospital) in Dhaka, Bangladesh. The male and female ratio was 7:5. Results: 92% of cases of the total number of patients had satisfactory removal/ neurological improvement/hormonal improvement. Among 12 cases, 8 cases had transient diabetes insipidus and one patient had CSF leak.    Conclusion: The intraoperative Doppler is a useful tool to localize the carotids, which provides safer resection of endonasal pituitary tumours. Thus, it is very safe and effective for laterosellar resection of recurrent pituitary tumours and for cavernous sinus invasions.

Prolactinomas and hyperprolactinaemia (including macroprolactinaemia)

2011 ◽  
pp. 187-197 ◽  
Author(s):  
John S. Bevan
Keyword(s):  
Growth Hormone ◽  
Management Strategies ◽  
Pituitary Tumour ◽  
Thyroid Stimulating Hormone ◽  
Pressure Effects ◽  
Type I ◽  
Local Pressure ◽  
Thyrotrophin Releasing Hormone ◽  
Pituitary Tumorigenesis ◽  
Pituitary Prolactin

Prolactin promotes milk production in mammals. It was characterized as a hormone distinct from growth hormone, which also has lactogenic activity, as recently as 1971. In humans, the predominant prolactin species is a 23 kDa, 199 amino acid polypeptide synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin is produced also by other tissues including decidua, breast, T lymphocytes, and several regions of the brain, where its functions are largely unknown and its gene regulation different from that of the pituitary gene. Pituitary prolactin production is under tonic inhibitory control by hypothalamic dopamine, such that pituitary stalk interruption produces hyperprolactinaemia. The neuropeptides thyrotrophin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) exert less important stimulatory effects on pituitary prolactin release (1). Following the discovery of prolactin as a separate hormone it became apparent that many apparently functionless ‘chromophobe’ pituitary adenomas were prolactinomas. Indeed, prolactinoma is the commonest type of functioning pituitary tumour diagnosed in humans. There is a marked female preponderance and prolactinoma is relatively rare in men. Several studies have revealed small prolactinomas in approximately 5% of autopsy pituitaries, most of which are undiagnosed during life. From a clinical standpoint, prolactinomas are divided arbitrarily into microprolactinomas (≤10 mm in diameter) and macroprolactinomas (>10 mm). This is a useful distinction which predicts tumour behaviour and indicates appropriate management strategies. Generally, microprolactinomas run a benign course. Some regress spontaneously, most stay unchanged over many years, and very few expand to cause local pressure effects. In contrast, macroprolactinomas may present with pressure symptoms, often increase in size if untreated and rarely disappear. Some clinicians find an intermediate category of meso-prolactinoma useful (10–20 mm in diameter), since this tumour group may have a more favourable treatment outcome than for larger macroprolactinomas. Prolactinomas are usually sporadic tumours. Molecular genetics has shown nearly all to be monoclonal, suggesting that an intrinsic pituitary defect is likely to be responsible for pituitary tumorigenesis (see Chapter 2.3.2). Occasionally, prolactinoma may be part of a multiple endocrine neoplasia syndrome type I, but this occurs too infrequently to justify screening in every patient with a prolactinoma. Mixed growth hormone and prolactin-secreting tumours are well recognized and give rise to acromegaly in association with hyperprolactinaemia. Most contain separate growth hormone and prolactin-secreting cells whereas a minority secrete growth hormone and prolactin from a single population of cells, the mammosomatotroph adenomas. Prolactin-secreting adenomas may produce other hormones such as thyroid-stimulating hormone (TSH) or adrenocorticotropic hormone (ACTH), but such tumours are uncommon. Malignant prolactinomas are also very rare. A few cases have been described which have proved resistant to aggressive treatment with surgery, radiotherapy, and dopamine agonists. In a small proportion, extracranial metastases in liver, lungs, bone, and lymph nodes have been documented. The alkylating agent temozolomide is effective against some aggressive prolactinomas (2).

scholarly journals Demethylation of somatic and testis-specific histone H2A and H2B genes in F9 embryonal carcinoma cells.

1993 ◽  
Vol 13 (9) ◽  
pp. 5538-5548 ◽  
Author(s):  
Y C Choi ◽  
C B Chae
Keyword(s):  
Embryonal Carcinoma ◽  
Cpg Island ◽  
Cpg Islands ◽  
High Density ◽  
Carcinoma Cells ◽  
Embryonal Carcinoma Cells ◽  
Cpg Dinucleotides ◽  
F9 Embryonal Carcinoma Cells ◽  
Methylation Patterns

In contrast to many other genes containing a CpG island, the testis-specific H2B (TH2B) histone gene exhibits tissue-specific methylation patterns in correlation with gene activity. Characterization of the methylation patterns within a 20-kb segment containing the TH2A and TH2B genes in comparison with that in a somatic histone cluster revealed that: (i) the germ cell-specific unmethylated domain of the TH2A and TH2B genes is defined as a small region surrounding the CpG islands of the TH2A and TH2B genes and (ii) somatic histone genes are unmethylated in both liver and germ cells, like other genes containing CpG islands, whereas flanking sequences are methylated. Transfection of in vitro-methylated TH2B, somatic H2B, and mouse metallothionein I constructs into F9 embryonal carcinoma cells revealed that the CpG islands of the TH2A and TH2B genes were demethylated like those of the somatic H2A and H2B genes and the metallothionein I gene. The demethylation of those CpG islands became significantly inefficient at a high number of integrated copies and a high density of methylated CpG dinucleotides. In contrast, three sites in the somatic histone cluster, of which two sites are located in the long terminal repeat of an endogenous retrovirus-like sequence, were efficiently demethylated even at a high copy number and a high density of methylated CpG dinucleotides. These results suggest two possible mechanisms for demethylation in F9 cells and methylation of CpG islands of the TH2A and TH2B genes at the postblastula stage during embryogenesis.

Pyrosequencing Analysis of the Methylation Status of the CpG Island in the Retinoic Acid Receptor-β2 (RAR-β2) Gene Promoter.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4297-4297
Author(s):  
Da-Cheng Zhou ◽  
David Reynolds ◽  
Robert E. Gallagher
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Cpg Island ◽  
Retinoic Acid Receptor ◽  
Methylation Status ◽  
Cpg Islands ◽  
Leukemia Cell ◽  
Gene Promoter ◽  
Cpg Dinucleotides ◽  
Retinoic Acid Receptor Β2

Abstract CpG islands are associated with the 5′-ends of most housekeeping genes and many regulated genes. We have hypothesized that the methylation status of CpG islands in the promoter region of all-trans retinoic acid (ATRA) target genes such as retinoic acid receptor-β2 (RAR-β2) may be related to ATRA resistance and relapse of acute promyelocytic leukemia (APL). In the present study, we developed a highly quantitative method to assess the degree of DNA methylation at specific sites using PyrosequencingTM technology (Biotage, Uppsala, Sweden). This method is more quantitative than methylation-specific PCR, and is as accurate as but simpler and more robust than combined bisulfite restriction analysis (COBRA) or direct sequencing of plasmid clones of PCR products. We used this method to study 14 CpG dinucleotides in the CpG island of the RAR-β2 promoter. In reconstruction experiments in which 100% methylated and 100% unmethylated DNAs were admixed in different proportions (100:0; 80:20, 60:40, etc), a straightline graph was obtained over the entire range from 0 – 100% for each of the 14 CpG dinucleotides (r2 &gt; 0.98). The results were highly reproducible and the variation between the results obtained from repetitive pyrosequencing of the same DNA was very low (S.D.&lt;2%). Also the standard deviation between measurements of different PCR-amplified, bisulfite-converted DNAs prepared in separate experiments was &lt;5%. We then used this method to measure the methylation level of the CpG island of the RAR-β2 promoter in several leukemia cell lines. Of 3 APL cell lines, the two with PML-RARα mutations, i.e., UF-1 and AP-1060, had higher overall methylation, compared to the NB4 cell line with non-mutant PML-RARα (mean ± SD = 52 ± 25% and 55 ± 21%, versus 43 ± 20%; p = 0.04 and 0.08, respectively; SD calculated from the variation across the 14 CpG dinucleotides for each source). Two myeloid leukemia cell lines with predominantly erythroid lineage characteristics, K562 and TF-1, had much lower levels of RAR-β2 methylation (2.6 ± 0.9% and 8.9 ± 3.2%, respectively). In the AP-1060 culture system, recently developed in our lab, there was little difference in methylation status between the patient bone marrow source and an intermediate, non-immortalized cell strain AP-1060S (27 ± 13% vs. 31 ± 25%). Further, there was no difference between lower and higher passage generations of AP-1060S (31 ± 25% vs. 30 ± 26%), which had markedly different replicative potential, indicating that replicative senescence at higher AP-1060 passages was not associated with altered methylation of the RAR-β2 gene promoter. However, the established, immortalized AP-1060 cell line had significantly greater methylation (52 ± 25%) than either the bone marrow source or AP-1060S (p &lt;0.0001 and p = 0.0002, respectively), consistent with published reports of increased promoter methylation of cell lines. In conclusion, pyrosequencing is a high throughput method with great quantitative strength, and can be used for accurate and consistent analysis of methylation status in large numbers of samples.

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