Pituitary Tumors


Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Oligonucleotide Array Sequence Analysis
  • Protein Kinase C-delta
  • Growth Hormone-Secreting Pituitary Adenoma
  • Case-Control Studies
  • Pedigree
  • Cell Proliferation
  • Neoplastic Cell Transformation
  • ASH1L
  • PLAGL1
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • GTP-Binding Protein alpha Subunits, Gs
  • Gene Expression Profiling
  • Magnetic Resonance Imaging
  • Germ-Line Mutation
  • Mutation
  • Biomarkers, Tumor
  • LRIG3
  • Prolactinoma
  • Pituitary ACTH Hypersecretion
  • Brain, Craniopharyngioma, Childhood
  • Receptors, CXCR
  • ACTH-Secreting Pituitary Adenoma
  • Genetic Predisposition
  • World Health Organization
  • Epigenetics
  • Pituitary Tumors
  • DNA Methylation
  • Multiple Endocrine Neoplasia Type 1
  • Immunohistochemistry
  • Neoplasm Invasiveness
  • MicroRNAs
  • Intracellular Signaling Peptides and Proteins
  • Adolescents
  • Cohort Studies
  • Acromegaly
  • DNA Mutational Analysis
  • Adenoma
  • Childhood Cancer
  • Gene Expression
  • Neoplasm Proteins
  • PTTG1
  • Proto-Oncogene Proteins c-kit
  • NNAT
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (31)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

POMC 2p23.3 LPH, MSH, NPP, POC, ACTH, CLIP -POMC and Pituitary Tumors
SSTR2 17q25.1 -SSTR2 and Pituitary Tumors
PRKAR1A 17q24.2 CAR, CNC, CNC1, PKR1, TSE1, ADOHR, PPNAD1, PRKAR1, ACRDYS1 -PRKAR1A and Pituitary Tumors
GHRH 20q11.23 GRF, INN, GHRF -GHRH and Pituitary Tumors
SSTR5 16p13.3 SS-5-R -SSTR5 and Pituitary Tumors
POU1F1 3p11 PIT1, CPHD1, GHF-1, Pit-1, POU1F1a -POU1F1 and Pituitary Tumors
MEG3 14q32.2 GTL2, FP504, prebp1, PRO0518, PRO2160, LINC00023, NCRNA00023, onco-lncRNA-83 -MEG3 and Pituitary Tumors
SSTR1 14q21.1 SS1R, SS1-R, SRIF-2, SS-1-R -SSTR1 and Pituitary Tumors
SSTR3 22q13.1 SS3R, SS3-R, SS-3-R, SSR-28 -SSTR3 and Pituitary Tumors
DRD2 11q23.2 D2R, D2DR -DRD2 and Pituitary Tumors
HMGA1 6p21.31 HMG-R, HMGIY, HMGA1A -HMGA1 and Pituitary Tumors
PYGM 11q13.1 -PYGM and Pituitary Tumors
NEUROD1 2q32 BETA2, BHF-1, MODY6, NEUROD, bHLHa3 -NEUROD1 and Pituitary Tumors
DLK1 14q32.2 DLK, FA1, ZOG, pG2, DLK-1, PREF1, Delta1, Pref-1 -DLK1 and Pituitary Tumors
PLAGL1 6q24.2 ZAC, LOT1, ZAC1 -PLAGL1 and Pituitary Tumors
PTTG1 5q33.3 EAP1, PTTG, HPTTG, TUTR1 -PTTG1 and Pituitary Tumors
ADCYAP1 18p11.32 PACAP -PACAP expression in Prostate Cancer
NNAT 20q11.23 Peg5 -NNAT and Pituitary Tumors
PITX1 5q31.1 BFT, CCF, POTX, PTX1, LBNBG -PITX1 and Pituitary Tumors
POLK 5q13.3 DINP, POLQ, DINB1 -POLK and Pituitary Tumors
AVPR1A 12q14.2 V1aR, AVPR1, AVPR V1a -AVPR1A and Pituitary Tumors
CHGA 14q32.12 CGA -CHGA and Pituitary Tumors
PDE11A 2q31.2 PPNAD2 -PDE11A and Pituitary Tumors
CNTF 11q12.1 HCNTF -CNTF and Pituitary Tumors
LAPTM4B 8q22.1 LC27, LAPTM4beta -LAPTM4B and Pituitary Tumors
WNT4 1p36.12 WNT-4, SERKAL -WNT4 and Pituitary Tumors
DKC1 Xq28 DKC, CBF5, DKCX, NAP57, NOLA4, XAP101 -DKC1 and Pituitary Tumors
LRIG3 12q14.1 LIG3 -LRIG3 and Pituitary Tumors
ASH1L 1q22 ASH1, KMT2H, MRD52, ASH1L1 -ASH1L and Pituitary Tumors
CCN5 20q13.12 CT58, WISP2, CTGF-L -WISP2 and Pituitary Tumors
AVPR1B 1q32.1 V1bR, AVPR3 -AVPR1B and Pituitary Tumors

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Okuda T, Fujita M, Kato A
Significance of Elevated HMGB1 Expression in Pituitary Apoplexy.
Anticancer Res. 2019; 39(8):4491-4494 [PubMed] Related Publications
BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation.
PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens.
RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478).
CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.

Sollfrank L, Lettmaier S, Erdmann M, Uslu U
Panniculitis Under Successful Targeted Inhibition of the MAPK/ERK Signaling Pathway in a Patient With BRAF V600E-mutated Spindle Cell Oncocytoma of the Pituitary Gland.
Anticancer Res. 2019; 39(7):3955-3959 [PubMed] Related Publications
BACKGROUND: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients.
CASE REPORT: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date.
CONCLUSION: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated.

Sidaraite A, Vilkeviciute A, Glebauskiene B, et al.
Association of ApoE haplotype with clinical evidence of pituitary adenoma.
Gene. 2019; 706:154-161 [PubMed] Related Publications
PURPOSE: To evaluate the association of the presence, invasiveness, hormonal activity and recurrence of pituitary adenoma (PA) with ApoE genotypes and alleles.
MATERIALS AND METHODS: Our study group included 142 patients with PA and the control group included 256 healthy individuals. The genotyping of ApoE (rs7412 and rs429358) was performed using a real-time PCR method.
RESULTS: After statistical analysis we found that ApoE genotype E2/E3 was associated with 2.6-fold increased odds of active PA (OR = 2.609; 95%CI: 1.380-4.932; p = 0.003), while the presence of ApoE E3/E3 decreased odds of active PA by 65% (OR = 0.343; 95%CI: 0.205-0.575; p < 0.001). The frequency of the allele ε3 was lesser in the PA group (74.3% vs. 83%, p = 0.003) when compared to controls but it was statistically significantly more frequent in the invasive PA than in the noninvasive PA subgroup (80.4% vs. 65.5%, p = 0.005). The ApoE E2/E4 genotype was more frequent in the noninvasive PA subgroup (10.3% vs. 0%, p = 0.003) than in the invasive PA subgroup. The ApoE E4/E4 genotype was more frequent in the recurrent than in the non-recurrent PA subgroup (6.6% vs. 0%, p = 0.006). No associations between ApoE polymorphisms and Ki-67 labelling index were found.
CONCLUSION: The ApoE E2/E3 genotype is associated with the presence of PA while the ApoE genotype E2/E4 is associated with noninvasive PA development. The allele ε3 could possibly have a protective effect against PA. The genotype E4/E4 is associated with the development of recurrent PA.

Rui QH, Ma JB, Liao YF, et al.
Effect of lncRNA HULC knockdown on rat secreting pituitary adenoma GH3 cells.
Braz J Med Biol Res. 2019; 52(4):e7728 [PubMed] Free Access to Full Article Related Publications
Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.

Hu A, Zhang Y, Zhao X, et al.
CBX1 is a direct target of miR-205-5p and contributes to the progression of pituitary tumor.
Pharmazie. 2019; 74(3):154-156 [PubMed] Related Publications
MicroRNAs (miRs) are crucial regulators for tumorigenesis through negatively regulating their target genes expression in the manner of 3'-untranslated region (3'-UTR) binding. MiR-205-5p has been reported to function as a tumor suppressor in several cancer types. The aim of this study was to investigate the role of miR-205-5p/chromobox homolog 1 (CBX1) axis in human pituitary tumors. The expression of miR-205-5p was firstly examined by quantitative real-time PCR and the results revealed that miR-205-5p expression was declined in pituitary cell lines compared with normal cell line. Overexpression of miR-205-5p effectively decreased cell proliferation and cell migration. Based on the results of bioinformatic analysis, luciferase reporter assay, and western blot, we identified CBX1 as a direct target of miR-205-5p. Notably, overexpression of CBX1 promoted cell proliferation and migration. The effects of miR-205-5p overexpression on cell proliferation and migration can be reversed by CBX1 overexpression. Based on these findings, we deducted that miR-205-5p inhibits the cell proliferation and migration through directly targeting CBX1.

Kim LH, Kim JH, Namgoong S, et al.
A PHLDB1 variant associated with the nonfunctional pituitary adenoma.
J Neurooncol. 2019; 142(2):223-229 [PubMed] Related Publications
PURPOSE: Previous studies have revealed that PHLDB1 single-nucleotide polymorphisms (SNPs) are associated with glioma risk. Nonetheless, the association between PHLDB1 SNPs and the risk of pituitary adenoma has not been studied. The present study evaluated the association of PHLDB1 SNPs with the risk of pituitary adenomas.
METHODS: We genotyped 27 PHLDB1 tagging and exon SNPs in a case-control study that included 148 patients who got a diagnosis of nonfunctional pituitary adenoma (NFPA) and 375 normal controls within the Korean population. Statistical analyses of the association between PHLDB1 SNPs and the NFPA risk were conducted using logistic regression.
RESULTS: We detected an association between a PHLDB1 SNP and the risk of NFPA in the Korean population. Rs67307131 in intron 2 was significantly associated with NFPA (odds ratio [OR] = 2.15, 95% confidence interval [CI] 1.44-3.20; P = 0.0002 in the dominant model). In the referent analysis, a higher OR and stronger association (lower P value) were observed among patients with the "C/T" genotype (OR = 2.39, 95% CI 1.60-3.58; P = 0.00002). In a functional analysis with a SNP annotation tool, this SNP was predicted to be a CpG site and copy number variant; these properties are associated with susceptibility to diseases.
CONCLUSIONS: Our findings suggest that genetic variation of PHLDB1 may be associated with the risk of NFPA. This is the first report of an association between PHLDB1 variants and NFPA. Further research is needed to confirm the impact of this SNP on NFPA susceptibility.

Corlan AS, Cîmpean AM, Melnic E, et al.
VEGF, VEGF165b and EG-VEGF expression is specifically related with hormone profile in pituitary adenomas.
Eur J Histochem. 2019; 63(1) [PubMed] Free Access to Full Article Related Publications
Vascular endothelial growth factor (VEGF), its inhibitory splice variant, VEGF165b and Endocrine Gland derived VEGF (EG-VEGF) have a controversial role in pituitary gland. We aim to study VEGF, VEGF165b and EG-VEGF expression in pituitary adenomas. A significant correlation was found between growth hormone (GH) and VEGF secretion (P=0.024). For prolactinomas, VEGF and prolactin expression, had a P-value of 0.02 for Kendall coefficient and a P-value of 0.043 for the Spearman coefficient. VEGF-mRNA amplification was detected in both tumor cells and folliculostellate cells. VEGF165b was positive in 16.66% of pituitary adenomas. EG-VEGF was significantly correlated with prolactin (P=0.025) and luteinizing hormone (P=0.028). Our data strongly support VEGF, VEGF165b and EG-VEGF as important players of pituitary adenomas tumorigenesis. Particular hormonal milieu heterogeneity, special vascular network with an unusual reactivity to tumor growth correlated with variability of VEGF, VEGF165b and EG-VEGF secretion may stratify pituitary adenomas in several molecular groups with a direct impact on therapy and prognosis.

Ságová I, Pávai D, Kantárová D, et al.
The combination of acromegaly and Klinefelter syndrome in one patient.
Vnitr Lek. Winter 2019; 65(1):51-54 [PubMed] Related Publications
Acromegaly is a rare disorder usually caused by a benign tumour of the pituitary gland. Long-term presence of elevated growth hormone (GH) and insulin like growth factor 1 (IGF1) levels accompanying this disease is associated with complications such as cardiomyopathy, diabetes mellitus, sleep apnoea and arthropathy. Incidence of acromegaly is 3-4 patients per million per year. Klinefelter syndrome (KS) is the most common sex chromosome disorder occuring in about 1/500 live male births. Common physical features include particularly small testes, among other symptoms are tall stature, reduced muscle tone, delayed pubertal development, lack of secondary male sex characteristics and gynecomastia. We present a 32-year-old man suffering from both acromegaly and 47, XXY Klinefelter syndrome. The patient with typical acromegalic features. Laboratory tests revealed high level of GH which was not suppressed after glucose administration, high level of IGF1, low testosterone concentration with high concentation of luteinizing hormone and follicle stimulating hormone. A magnetic resonance imaging scan revealed a 25 × 18 × 18 mm macroadenoma involving the pituitary gland. A diagnosis of acromegaly was established. After this examination trans-sphenoidal resection was performed. Histopathologic and immunohistochemical findings revealed growth hormoneproducing pituitary adenoma. The presence of infertility with clinical features such as small testes, lack of secondary male sex characteristics and laboratory findings revealed hypergonadotropic hypogonadism that could not be explained by the diagnosis of acromegaly. A chromosomal karyotyping revealed a 47, XXY, confirming the diagnosis of KS. Testosterone replacement therapy wasn´t begun because of patient disagreement Postoperatively elevated plasma concentration of GH and IGF1 levels persist. Treatment by somatostatin analogues (lanreotid) was initiated at dose 120 mg every 28 days. Control magnetic resonance imaging of the sella demonstrated a residue of pituary adenoma size 14 × 14 × 7 mm. The patient is currently undergoing endoscopic revision of the residue. acromegaly - growth hormone - IGF1 - Klinefelter syndrome - testosterone.

Yarman S, Tuncer FN, Serbest E
Three Novel MEN1 Variants in AIP-Negative Familial Isolated Pituitary Adenoma Patients.
Pathobiology. 2019; 86(2-3):128-134 [PubMed] Related Publications
OBJECTIVES: Pituitary adenomas (PAs) may rarely occur in well-defined hereditary conditions, like multiple endocrine neoplasia type 1 (MEN1) syndrome and familial isolated pituitary adenoma (FIPA) associated with germline mutations in MEN1 and AIP, respectively. This study aimed to assess MEN1 genetic abnormalities in AIP mutation-negative FIPA patients, not associated with MEN1 components.
METHODS: Among 20 patients evaluated in 13 FIPA families, 12 were previously reported as AIP mutation-negative. In this study, 6 new families with 8 patients were recruited. All patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in AIP and MEN1, and AIP sequencing was performed in additional patients. AIP mutation-negative patients were subjected to MEN1 sequencing.
RESULTS: Our cohort revealed only 3 novel heterozygous MEN1 variants including c.1846T>A p.(*616Argext*21), rs778272737:T>C, and rs972128957:C>T in 2 families, with patients diagnosed with Cushing disease, nonfunction al adenoma, and acromegaly, respectively. Among them, c.1846T>A p. (*616Argext*21) is a stop codon read-through, whereas the others are 3'UTR variations. MEN1 variation frequency was detected as 15%.
CONCLUSIONS: MEN1 alterations can be of significance in FIPA patients and screening could be offered to AIP mutation-negative patients without MEN1 features. Further studies are needed to clarify the role of MEN1 in FIPA patients.

Capatina C, Cimpean AM, Raica M, et al.
SOX 2 Expression in Human Pituitary Adenomas-Correlations With Pituitary Function.
In Vivo. 2019 Jan-Feb; 33(1):79-83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: The aim of this study was to evaluate SOX2 expression in pituitary adenomas and its correlation to their secretory state and clinicopathological parameters.
PATIENTS AND METHODS: Thirty-four patients were clinically evaluated and surgery was recommended for tumor removal. Histopathological diagnosis by hematoxylin eosin staining was followed by immunohistochemistry for pituitary hormones and SOX2 co-expression.
RESULTS: Fourteen of the 34 cases were GH-secreting adenomas, 10 were prolactinomas and 10 non-functioning pituitary adenomas. SOX2-positive expression was detected in 47.05% of total cases: 8 GH-secreting adenomas (57.14%), 6 prolactinomas (60%) and 2 non-functioning adenomas (20%). SOX2 positivity was significantly higher amongst secreting adenomas (p=0.041). SOX2-negative tumors were significantly associated with corticotrophin deficiency (p=0.047) and gonadotrophin deficiency (p=0.041). No correlation with tumor size or extrasellar extension was detected.
CONCLUSION: SOX2 is differentially expressed in pituitary adenomas and influences the secretory state or clinical behavior of pituitary adenomas.

Cai F, Hong Y, Xu J, et al.
A Novel Mutation of Aryl Hydrocarbon Receptor Interacting Protein Gene Associated with Familial Isolated Pituitary Adenoma Mediates Tumor Invasion and Growth Hormone Hypersecretion.
World Neurosurg. 2019; 123:e45-e59 [PubMed] Related Publications
BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in nearly 20% of families with familial isolated pituitary adenoma. Some variants of AIP have been confirmed to induce tumor cell proliferation and invasiveness; however, the mechanism is still unclear.
METHODS: A novel missense mutation (c.512C>T, p.T171I) was discovered in 3 patients from a Chinese family with familial isolated pituitary adenoma. In silico and multiplex ligation-dependent probe amplification analysis predicted the mutation to be pathogenic. GH3 and 293FT cell lines were used to verify the variant's effect on cell proliferation (Cell Counting Kit-8), invasiveness (Transwell) and growth hormone (GH) secretion (enzyme-linked immunosorbent assay) by transfection with different vectors: control, blank vector, wild-type AIP, p.T171I variant (experimental group), p.Q315* variant, and AIP small interfering RNA. Furthermore, Zac1, Sstr2, interleukin (IL)-6, and Stat3/phosphorylation-Stat3 expression (reverse transcription polymerase chain reaction, Western blot) in each group was also evaluated.
RESULTS: The experimental group, p.Q315* variant group, and AIP small interfering RNA-overexpressing group promoted cell proliferation at 24 and 48 hours, respectively (compared with the control group; P < 0.01 for both). Similarly, the cells in the experimental group manifested more invasion and GH secretion compared with the control group (P < 0.01 and P < 0.05, respectively). Furthermore, the experimental group cells expressed less Sstr2 (a prerequisite for the responsiveness to somatostatin analogues) and Zac1 (tumor suppressor gene), but more IL-6 and phosphorylated-Stat3 (GH-secretion related).
CONCLUSIONS: The novel AIP mutation c.512C>T (p.T171I) is a pathogenic variant that promoted cell proliferation, invasiveness, and GH secretion through regulation of Sstr2, Zac1, and IL-6/phosphorylated-Stat3 expression.

Marini F, Giusti F, Brandi ML
Multiple endocrine neoplasia type 1: extensive analysis of a large database of Florentine patients.
Orphanet J Rare Dis. 2018; 13(1):205 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple endocrine neoplasia (MEN1) is a rare inherited multi-tumour syndrome, affecting specific neuroendocrine organs and non-endocrine tissues with a variable spectrum of over 20 possible different combinations, caused by inactivating heterozygote mutations of the MEN1 gene. Disease onset, penetrance, clinical presentation, course and prognosis are all extremely variable, even among individuals bearing the same causative mutation, which doesn't allow prediction of the individual clinical phenotype (based on the specific result of the genetic test), thus compelling all patients and mutation carriers to undergo a common routine general screening program.
RESULTS: We performed an extensive epidemiological, clinical and genetic analysis of the Florentine MEN1 patient database, which includes 145 MEN1 patients and 20 asymptomatic MEN1 carriers, constantly followed up at the Regional Referral Centre for Inherited Endocrine Tumours of the Tuscany Region, during the last three decades. We reported, here, the results of clinical, epidemiological and genetic descriptive statistics, as well as correlation analyses between tumours and mutation types and localisation. No direct genotype-phenotype correlation was described, but the importance of the genetic testing was confirmed for an early diagnosis and the identification of asymptomatic carriers.
CONCLUSIONS: As with all rare diseases, the possibility to collect and analyse data on a relatively large number of patients is important for increasing our knowledge of the epidemiologic aspects of the disease, and its natural course and prognosis of single manifestations of the syndrome, in order to set up the best diagnostic and therapeutic plans for patients. In this light, the creation and constant updating of large patient databases is fundamental. Results from database study can provide useful epidemiological, clinical and genetic information about MEN1 syndrome, which could help clinicians in the diagnostic and therapeutic management of single MEN1 patients.

Miyake Y, Adachi JI, Suzuki T, et al.
TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas.
J Neurooncol. 2019; 141(1):131-138 [PubMed] Related Publications
PURPOSE: Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables.
METHODS: We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR.
RESULTS: TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters.
CONCLUSIONS: This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.

Beckers A, Petrossians P, Hanson J, Daly AF
The causes and consequences of pituitary gigantism.
Nat Rev Endocrinol. 2018; 14(12):705-720 [PubMed] Related Publications
In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.

Amorim PVGH, Grande IPP, Batista RL, et al.
Association between KISS1 rs5780218 promoter polymorphism and onset of growth hormone secreting pituitary adenoma.
Ann Endocrinol (Paris). 2019; 80(2):96-100 [PubMed] Related Publications
OBJECTIVES: This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples.
RESULTS: The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P<0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA.
CONCLUSIONS: In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.

Gao M, Zhu B, Xu Z, et al.
Association between acromegaly and a single nucleotide polymorphism (rs2854744) in the IGFBP3 gene.
BMC Med Genet. 2018; 19(1):182 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It has been reported that the single nucleotide polymorphism (SNP) rs2854744 at the - 202 locus of insulin-like growth factor binding protein-3 (IGFBP3) is associated with serum levels and a number of malignancies. However, the effect of IGFBP3 gene polymorphism on acromegaly is less clear. Therefore, in the current study, we aimed to investigate whether the -202A/C polymorphism of IGFBP3 constitutes a risk factor for acromegaly.
METHODS: The study included 102 acromegalic patients and 143 control subjects in Beijing Tiantan Hospital. The genotyping of IGFBP3 was carried out using the MassARRAY method. Serum IGFBP3 concentrations were also determined. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the associations of genetic polymorphisms with the development of acromegaly and its different subtypes.
RESULTS: The study revealed that the C allele of rs2854744 was associated with a reduced risk of acromegaly (OR 0.594, 95% CI 0.388-0.909), as well as with the female (OR 0.385, 95% CI 0.206-0.72), macroadenoma (OR 0.557, 95% CI 0.347-0.893) and monotherapy (OR 0.512, 95% CI 0.316-0.828) subgroups under the additive model. A higher serum IGFBP3 level was observed in patients with the AA genotype, but this difference was not significant (P = 0.331).
CONCLUSION: This study is one of the first to show that the IGFBP3 polymorphism may have an influence on serum levels and that the C allele of rs2854744 is associated with a reduced risk of acromegaly. This correlation was more prominent in females, those with large tumours and those treated with monotherapy in a Chinese population. Genetic polymorphism of IGFBP3 may be involved in the development of acromegaly.

Lobatto DJ, Steffens ANV, Zamanipoor Najafabadi AH, et al.
Work disability and its determinants in patients with pituitary tumor-related disease.
Pituitary. 2018; 21(6):593-604 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Pituitary tumors may have a considerable impact on patients' functional status, including paid employment, yet research in this area is sparse.
OBJECTIVE: To describe work disability and its determinants in patients treated for a pituitary tumor.
METHODS: Cross-sectional study including patients treated for a pituitary tumor in the working age (18-65 years), who completed five validated questionnaires assessing work disability [Short Form-Health and Labour Questionnaire, Work Role Functioning Questionnaire 2.0 (WRFQ)], health-related quality of life (HRQoL) and utility (Short Form-36, EuroQoL) and disease burden (Leiden Bother and Needs Questionnaire-Pituitary). Additional data were extracted from the medical records (age, gender, tumor type, treatment, date of diagnosis) and self-reports (marital status, education, endocrine status). Associations of disease-specific and sociodemographic characteristics, HRQoL, and disease burden with (not) having a paid job were examined through multivariate logistic regression.
RESULTS: We included 241 patients (61% female, median age 53 years, median time since diagnosis 11 years), of whom 68 (28%) were without a paid job. Patients who had acromegaly, Cushing's disease, (pan)hypopituitarism, radiotherapy, were single, less educated, lower HRQoL, and increased disease burden were more often without a paid job (p < 0.05). Among those with paid jobs, 41% reported health-related absenteeism in the previous year. The three work incapacitating problems reported by the largest proportion of patients were within the mental and social domain (WRFQ).
CONCLUSION: Work disability among patients treated for a pituitary tumor is substantial. As impact on social functioning is high, it is strongly advised to incorporate work disability during clinical guidance of patients.

He C, Yang J, Ding J, et al.
Downregulation of glucose‑6‑phosphate dehydrogenase by microRNA‑1 inhibits the growth of pituitary tumor cells.
Oncol Rep. 2018; 40(6):3533-3542 [PubMed] Related Publications
Pituitary tumors are generally intracranial neoplasms with high incidence and mortality rates. The investigation of novel factors involved in the tumorigenesis of pituitary tumors and the characterization of the underlying molecular mechanisms is urgently required for the diagnosis and treatment of pituitary tumors. Accumulating evidence has indicated that microRNAs (miRs) serve important roles in the initiation and progression of cancer. The present study found that miR‑1 was significantly downregulated in pituitary tumor tissues upon reverse transcription‑quantitative polymerase chain reaction analysis. Decreased expression of miR‑1 was associated with the progression and worse prognosis of patients with pituitary tumors. The MTT assay showed that overexpression of miR‑1 significantly suppressed proliferation. Highly expressed miR‑1 promoted the apoptosis of pituitary tumor cells upon fluorescence‑activated cell sorting analysis. Further molecular study revealed that glucose‑6‑phosphate dehydrogenase (G6PD), the first and rate‑limiting enzyme of the pentose phosphate pathway (PPP), was one of the targets of miR‑1. Western blot assays showed that overexpression of miR‑1 significantly decreased the protein level of G6PD in pituitary tumor cells without changing the mRNA level of G6PD. Consequently, oxidative PPP flux analysis revealed that suppression of G6PD by miR‑1 decreased the production of nicotinamide adenine dinucleotide phosphate and the glycolysis of pituitary cancer cells. Restoration of the expression of G6PD significantly reversed the inhibitory effect of miR‑1 on the PPP and the growth of pituitary tumor cells. Collectively, the present results uncovered the critical involvement of miR‑1 in pituitary tumors, indicating that miR‑1 is a potential therapeutic target for the treatment of pituitary tumors.

Dennison KL, Chack AC, Hickman MP, et al.
Ept7, a quantitative trait locus that controls estrogen-induced pituitary lactotroph hyperplasia in rat, is orthologous to a locus in humans that has been associated with numerous cancer types and common diseases.
PLoS One. 2018; 13(9):e0204727 [PubMed] Free Access to Full Article Related Publications
Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals at autopsy. Prolactin-producing adenomas, i.e., prolactinomas, comprise approximately 50% of all pituitary adenomas and represent the most common class of pituitary tumor. Multiple observations suggest that estrogens may contribute to development of prolactinoma; however, direct evidence for a causal role of estrogens in prolactinoma etiology is lacking. Rat models of estrogen-induced prolactinoma have been utilized extensively to identify the factors, pathways and processes that are involved in pituitary tumor development. The objective of this study was to localize to high resolution Ept7 (Estrogen-induced pituitary tumor), a quantitative trait locus (QTL) that controls lactotroph responsiveness to estrogens and was mapped to rat chromosome 7 (RNO7) in an intercross between BN and ACI rats. Data presented and discussed herein localize the Ept7 causal variant(s) to a 1.91 Mb interval of RNO7 that contains two protein coding genes, A1bg and Myc, and Pvt1, which yields multiple non-protein coding transcripts of unknown function. The Ept7 orthologous region in humans is located at 8q24.21 and has been linked in genome wide association studies to risk of 8 distinct epithelial cancers, including breast, ovarian, and endometrial cancers; 3 distinct types of B cell lymphoma; multiple inflammatory and autoimmune diseases; and orofacial cleft defects. In addition, the Ept7 locus in humans has been associated with variation in normal hematologic and development phenotypes, including height. Functional characterization of Ept7 should ultimately enhance our understanding of the genetic etiology of prolactinoma and these other diseases.

Zhu B, Wang J, Qin L, et al.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
The association of the fibroblast growth factor receptor 2 gene (

Brown OA, Canatelli-Mallat M, Console GM, et al.
IGF-1 Gene Therapy as a Potentially Useful Therapy for Spontaneous Prolactinomas in Senile Rats.
Curr Gene Ther. 2018; 18(4):240-245 [PubMed] Related Publications
BACKGROUND: Insulin-like Growth Factor1 (IGF1) is a powerful neuroprotective molecule. We have previously shown that short-term hypothalamic IGF1 gene therapy restores tuberoinfundibular dopaminergic neuron function in aging female rats.
OBJECTIVE: Our aim was to implement long-term IGF-I gene therapy in pituitary prolactinomas in senile female rats.
METHODS: Here, we assessed the long-term effect of IGF1 gene therapy in the hypothalamus of young (4 mo.) and aging (24 mo.) female rats carrying spontaneous pituitary prolactinomas. We constructed and injected a Helper-Dependent (HD) adenovector expressing the gene for rat IGF1 or the reporter red fluorescent protein DsRed. Ninety-one days post vector injection, all rats were sacrificed and their brains and pituitaries fixed. Serum prolactin (PRL), Estrogen (E2) and progesterone (P4), as well as hypothalamic IGF1 content, were measured by RIA. Anterior pituitaries were immunostained with an anti-rat PRL antibody and submitted to morphometric analysis.
RESULTS: DsRed expression in the Mediobasal Hypothalamus (MBH) was strong after the treatment in the DsRed group while IGF1 content in the MBH was higher in the IGF1 group. The IGF1 treatment affected neither pituitary weight nor PRL, E2 or P4 serum levels in the young rats. In the old rats, IGF1 gene therapy reduced gland weight as compared with intact counterparts and tended to reduce PRL levels as compared with intact counterparts. The treatment significantly rescued the phenotype of the lactotropic cell population in the senile adenomas.
CONCLUSION: We conclude that long-term hypothalamic IGF1 gene therapy is effective to rescue spontaneous prolactinomas in aging female rats.

Saavedra A, Lima J, Castro L, et al.
Malignant paraganglioma and somatotropinoma in a patient with germline SDHB mutation-genetic and clinical features.
Endocrine. 2019; 63(1):182-187 [PubMed] Related Publications
BACKGROUND: Pituitary adenomas and paragangliomas/pheocromocytomas are rare endocrine tumours, which can be sporadic or familial. During many years their coexistence in the same individual was considered a coincidental finding. However, an association between these two entities was recently demonstrated, with the possible involvement of SDHx genes.
CASE REPORT: We describe a 57-year-old female patient, who was under surveillance since 1997 for a malignant paraganglioma with vertebral bone metastasis, and harboured a germline frameshift mutation in exon 6 of SDHB gene [c.587-591DelC]. Seventeen years later, she was diagnosed with acromegaly and underwent transesphenoidal endoscopic resection of a somatotropinoma. Three months after surgery she started treatment with lanreotide for residual disease. Despite initial good response, she developed resistance to first generation of somatostatin analogues and treatment had to be switched to pegvisomant. In the immunohistochemical staining, the pituitary adenoma was positive for SDHA expression, while SDHB showed an heterogeneous staining pattern, with areas markedly positive and others with positive and negative cells.
CONCLUSIONS: Our findings provide useful data for understanding the link between paragangliomas/pheocromocytomas and somatotropinomas. While we confirm the well-established link between SDHB mutations and paragangliomas/pheocromocytomas, particularly with malignant paragangliomas, the preservation-at least partially-of SDHB expression in the somatotropinoma tissue does not allow drawing definite conclusions about the involvement of the SDHB mutation in pituitary adenoma.

Lin AL, Jonsson P, Tabar V, et al.
Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab.
J Clin Endocrinol Metab. 2018; 103(10):3925-3930 [PubMed] Free Access to Full Article Related Publications
Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options.
Case: A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL.
Molecular Evaluation: Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation.
Conclusion: Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M
Endocr Pract. 2018; 24(10):907-914 [PubMed] Related Publications
OBJECTIVE: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.
METHODS: Literature review.
RESULTS: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 ( USP8) gene in almost half of Cushing disease tumors.
CONCLUSION: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.
ABBREVIATIONS: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8.

Wang H, Wang G, Gao Y, et al.
Lnc-SNHG1 Activates the TGFBR2/SMAD3 and RAB11A/Wnt/β-Catenin Pathway by Sponging MiR-302/372/373/520 in Invasive Pituitary Tumors.
Cell Physiol Biochem. 2018; 48(3):1291-1303 [PubMed] Related Publications
BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer and could function as competing endogenous RNAs (ceRNAs) to regulate microRNAs (miRNAs).
METHODS: Quantitative real-time PCR (qRT-PCR) was used to analyze the expression of lnc-SNHG1 and miR-302/372/373/520 in pituitary tumor tissues and cell lines. Cell proliferation was investigated using MTT and cell count assays. The mechanisms by which lnc-SNHG1 affects pituitary tumor progression were investigated using Western blot assays, transwell migration assays, immunohistochemistry, immunofluorescence, luciferase reporter assays, tumor xenografts, and flow cytometry Results: We found that lnc-SNHG1 was overexpressed in invasive pituitary tumor tissues and cell lines. Ectopic expression of lnc-SNHG1 promoted cell proliferation, migration, and invasion, as well as the epithelial-mesenchymal transition (EMT), by affecting the cell cycle and cell apoptosis in vitro and tumor growth in vivo. Further study indicated that overexpression of lnc-SNHG1 markedly inhibited the expression of miR-302/372/373/520 (miRNA-pool) which is down-regulated in invasive pituitary tumor cells. Moreover, overexpression of lnc-SNHG1 significantly promoted the expression of TGFBR2 and RAB11A, the direct targets of miR-302/372/373/520. Finally, lnc-SNHG1 activates the TGFBR2/SMAD3 and RAB11A/Wnt/β-catenin pathways in pituitary tumor cells via sponging miR-302/372/373/520.
CONCLUSIONS: Our data suggest that lnc-SNHG1 promotes the progression of pituitary tumors and is a potential therapeutic target for invasive pituitary tumor.

Polidoro MA, Rotondi S, Morace R, et al.
Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells.
Horm Metab Res. 2018; 50(8):640-647 [PubMed] Related Publications
Peroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA - 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) - were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100-200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.

Ma HS, Wang EL, Xu WF, et al.
Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas.
Med Sci Monit. 2018; 24:4841-4850 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas. MATERIAL AND METHODS We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs. RESULTS Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high-methylation status persisted after adjusting for clinicopathological features. CONCLUSIONS Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma.

DeVore SB, Young CH, Li G, et al.
Histone Citrullination Represses MicroRNA Expression, Resulting in Increased Oncogene mRNAs in Somatolactotrope Cells.
Mol Cell Biol. 2018; 38(19) [PubMed] Free Access to Full Article Related Publications
Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas are unknown. To begin to address these issues, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4, and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA sequencing and chromatin immunoprecipitation (ChIP) studies show that the expression of microRNAs (miRNAs) let-7c-2, 23b, and 29c is suppressed by histone citrullination. Our studies demonstrate that these miRNAs directly target the mRNA of the oncogenes encoding HMGA, insulin-like growth factor 1 (IGF-1), and N-MYC, which are highly implicated in human prolactinoma/somatoprolactinoma pathogenesis. Our results are the first to define a direct role for PAD-catalyzed histone citrullination in miRNA expression, which may underlie the etiology of prolactinoma and somatoprolactinoma tumors through regulation of oncogene expression.

García-Martínez A, Sottile J, Fajardo C, et al.
Is it time to consider the expression of specific-pituitary hormone genes when typifying pituitary tumours?
PLoS One. 2018; 13(7):e0198877 [PubMed] Free Access to Full Article Related Publications
The aim of the present study is to check whether we can replicate, in an independent series, previous results showing that the molecular study of pituitary-specific gene expression complements the inmunohistochemical identification of pituitary neuroendocrine tumours. We selected 112 patients (51 (46.4%) women; mean age 51.4±16 years; 102 macroadenomas (91.9%), 9 microadenomas (8.1%)) with complete clinical, radiological, immunohistochemical and molecular data from our data set of pituitary neuroendocrine tumours. Patients were different from those previously studied. We measured the expression of the pituitary-specific hormone genes and type 1 corticotrophin-releasing hormone and arginine vasopressin 1b receptors, by quantitative real-time polymerase chain reaction using TaqMan probes. Afterwards, we identified the different pituitary neuroendocrine tumour subtypes following the 2017 World Health Organization classification of pituitary tumours, calculating the concordance between their molecular and immuhistochemical identification. The concordance between molecular and immunohistochemical identification of functioning pituitary neuroendocrine tumours with the clinical diagnosis was globally similar to the previous series, where the SYBR Green technique was used instead of TaqMan probes. Our results also corroborated the poor correlation between molecular and immunohistochemical detection of the silent pituitary neuroendocrine tumour variants. This discrepancy was more remarkable in lactotroph, null-cell and plurihormonal pituitary neuroendocrine tumours. In conclusion, this study validates the results previously published by our group, highlighting a complementary role for the molecular study of the pituitary-specific hormone genes in the typification of pituitary neuroendocrine tumours subtypes.

Joshi K, Daly AF, Beckers A, Zacharin M
Resistant Paediatric Somatotropinomas due to AIP Mutations: Role of Pegvisomant.
Horm Res Paediatr. 2018; 90(3):196-202 [PubMed] Related Publications
BACKGROUND: Somatotropinomas are rare in childhood and frequently associated with genetic mutations. AIP mutations are found in 20-25% cases and cause aggressive somatotropinomas, often resistant to somatostatin analogues.
AIMS: To assess responses to multimodal therapy including pegvisomant in 2 children with sporadic somatotropinomas due to AIP mutations.
CASE DESCRIPTION: We report 2 children, a boy aged 13 and a girl aged 10, with rapid growth, visual impairment, and growth hormone hypersecretion. Magnetic resonance imaging confirmed a pituitary macroadenoma with parasellar extension in both. Despite multiple surgical attempts to debulk tumour mass, residual tumour persisted. Genetic analysis showed two different AIP mutations (patient 1: c.562delC [p.Arg188Glyfs*8]; patient 2: c.140_ 163del24 [p.Gly47_Arg54del8]). They were initially treated with a long-acting somatostatin analogue (octreotide LAR 30 mg/month) and cabergoline as a dopamine agonist, with the later addition of pegvisomant titrated up to 20 mg/day and with radiotherapy for long-term control. Somatostatin analogue was ceased due to patient intolerance and lack of control. Patient 1 had normalization of insulin-like growth factor-1 (IGF-1) after 5 months of combined therapy with pegvisomant and cabergoline. For patient 2, normalization of IGF-1 was achieved after 2 months of cabergoline and pegvisomant.
CONCLUSION: AIP-associated tumours can be resistant to management with somatostatin analogues. Pegvisomant can safely be used, to normalize IGF-1 levels and help control disease.

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