Expression of cAMP and oxidative phosphorylation-related lncRNAs in non-functioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) are benign lesions in the pituitary gland with important morbidities. In this study, based on a bioinformatics analysis to identify the genes and pathways that display significant differences between tumour tissues of NFPA patients and normal pituitary tissues, we selected lncRNAs related to cAMP and oxidative phosphorylation pathways, namely DNAH17-AS1, LINC00706 and SLC25A5-AS1. Then, we aimed to investigate by means of RT-qPCR, the expression of these lncRNAs along with two other lncRNAs, namely CADM3-AS1 and MIR7-3HG in NFPA samples compared to that in healthy tissues adjacent to the tumours. Transcripts of DNAH17-AS1, LINC00706 and MIR7-3HG were lower in NFPA samples compared with controls (Expression ratios (95% CI) = 0.43 (0.23-0.78), 0.58 (0.35-0.96) and 0.58 (0.35-0.96); p-values = 0.009, 0.025 and 0.036, respectively). AUC values of ROC curves of DNAH17-AS1, LINC00706 and MIR7-3HG were 0.62, 0.61 and 0.62, respectively. Expression of CADM3-AS1 was associated with the gender of patients in a way that it was lower in female patients (p-value = 0.04). The level of SLC25A5-AS1 was lower in subjects with disease duration lower than 1 year (p-value = 0.048). We showed dysregulation of three lncRNAs in NFPA tissues and potentiates these lncRNAs as important regulators of pathogenic events in these tumours.

Refractory nonfunctioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) comprise silent tumors of different pituitary lineages that tend to escape early detection and present as invasive macroadenomas with symptoms of mass effect. Incomplete surgical resection is common and may be followed by significant rates of subsequent remnant progression. Pituitary tumors are defined as refractory when resistance to optimal standard therapies including surgery, radiotherapy, and medical treatment is documented. In the absence of approved medications for the treatment of NFPAs, the last criterion to classify these tumors as refractory is ill defined. Silent corticotroph and null cell adenomas have been reported, albeit not in all studies, to be larger and recur more often compared with silent gonadotroph tumors. Nevertheless, it is currently unknown if certain NFPA subtypes are more often refractory using well defined criteria. The response rate to temozolomide is lower in NFPA compared to that seen in functioning tumors. Refractory NFPAs present a significant diagnostic and therapeutic challenge and are associated with increased morbidity and mortality rates.

The silent variants of pituitary tumors: demographic, radiological and molecular characteristics.

INTRODUCTION: Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known. AIM: To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression. METHODS: This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR. RESULTS: We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations. CONCLUSIONS: This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

Low-dose ACTH test for evaluation of hypothalamus-pituitary-adrenal axis preoperatively and 3-month follow-up in non-functioning pituitary adenomas.

BACKGROUND: Peri-operative glucocorticoids are routinely administered to patients undergoing trans-sphenoidal surgery for non-functional pituitary adenomas (NFPA) irrespective of hypothalamus-pituitary-adrenal (HPA) axis status. PURPOSE: Evaluation of HPA axis before and 12 weeks after endoscopic trans-sphenoidal adenomectomy (E-TSA) utilizing low-dose (1 µg) ACTH stimulation test (LDACTH) to determine the need for glucocorticoid administration in patients with NFPA. We also determined the factors that can predict occurrence of hypocortisolism at 12 weeks after surgery. METHODS: Sixty-three consecutive patients with NFPA requiring surgical excision were enrolled in this study. Glucocorticoids were administered to patients with demonstrable hypocortisolism [preoperative peak cortisol < 16 µg/dL during LDACTH test, postoperative day 3 (POD-3) 0800 hrs Cortisol < 8 µg/dL or stimulated cortisol (LDACTH) < 16 µg/dL at 12 weeks]. RESULTS: Hypocortisolism was present in 43 patients (68.2%) pre-operatively and persisted in 33 patients (52.4%) on POD-3. Thirty-three patients (52.4%) had hypocortisolism at 12 weeks after surgery. Eleven patients (17.4%) did not require glucocorticoids during the entire study period and 30 patients (47.6%) did not require glucocorticoids after 3 months. None of the patients developed adrenal crisis during the study. Hypocortisolism on the third post-operative day was the single significant predictor of hypocortisolism at 12 weeks after the surgery. There was a significant correlation between POD-3 0800 hrs cortisol ≥ 8µg/dL and stimulated cortisol (LDACTH) ≥16µg/dL at 12 weeks (r = 0.62, p < 0.0001). POD-3 0800 hrs cortisol ≥ 8 µg/dL had 73% sensitivity and 79% specificity in predicting eucortisolism at 12 weeks. CONCLUSIONS: HPA function is preserved in significant proportion of NFPA patients undergoing E-TSA. Perioperative glucocorticoids should be given only in patients with demonstrable preoperative hypocortisolism on 1 µg ACTH test. Postoperative day 3 0800 hrs cortisol is a reasonable predictor of HPA axis status at 12 weeks after surgery.

Preoperative growth hormone (GH) peak values during a GH releasing peptide-2 test reflect the severity of hypopituitarism and the postoperative recovery of GH secretion in patients with non-functioning pituitary adenomas.

Non-functioning pituitary adenoma (NFPA) is one common cause of adult growth hormone deficiency (AGHD). In Japan, a GH-releasing peptide (GHRP)-2 test is used to evaluate GH secretion. Although the cut-off for peak GH during a GHRP-2 test for severe AGHD is ≤9 ng/mL, severe AGHD may further diminish responses (range, nearly no-response to ≤9 ng/mL). We studied whether the peak GH responses during a GHRP-2 test could be predicted based on clinical characteristics of patients with NFPA. We compared patients with almost no-response during a GHRP-2 test with other patients considered as severe AGHD. Among the 76 patients with NFPA who were admitted to our institution, 36 patients (mean age, 61 years; male/female, n = 23/n = 13) were diagnosed with severe AGHD based on a preoperative GHRP-2 test. Based on the preoperative median peak GH concentration (2.83 ng/mL), patients were divided into two groups (

Quality of life is significantly impaired in both secretory and non-functioning pituitary adenomas.

OBJECTIVE: To evaluate the quality of life (QoL) in patients with pituitary adenomas in comparison with healthy Mexican population QoL scores. DESIGN & MEASUREMENTS: Cross-sectional study using the short form 36 questionnaire (SF-36) in 175 patients with pituitary adenomas grouped by adenoma subtype and disease activity, and compared them with the healthy Mexican population normative QoL scores. PATIENTS: A total of 44 patients with non-functioning pituitary adenomas (NFPA), 48 with acromegaly, 53 with prolactinomas and 30 with Cushing disease (CD) were enrolled in this study. RESULTS: Mental and physical components scores (MCS & PCS) of SF-36 questionnaire were lower in patients with active disease in all adenoma subtypes (P < 0.03). A significant negative relationship between prolactin levels and MCS (r = -0.30, P < 0.01) and PCS (r = -0.41, P < 0.01) were found in prolactinomas. Patients with CD showed 24 hours urine-free cortisol levels negatively correlated with MCS (r = -0.43, P < 0.01) but not with PCS. No significant correlation was found between IGF-1 ULN and QoL scores in acromegaly. NFPA patients had lower QoL scores than patients with controlled CD, acromegaly or prolactinoma (P < 0.02). Active CD and prolactinoma have lower QoL scores in comparison of NFPA (P < 0.05). Having an adenoma, secretory or non-functioning, decrease QoL scores in comparison of results in the healthy Mexican population register. Using an adjusted-multivariate model, we confirmed that disease activity in all secretory adenomas is an independent risk factor, reducing SF-36 scores significantly. CONCLUSION: Activity in all secretory pituitary adenomas' patients decrease mental and physical QoL. However, independently of disease activity, secretory and NFPA significantly decrease QoL in comparison with healthy Mexican population QoL register.

Gene and protein expression of E-cadherin and NCAM markers in non-functioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPA) are classified as benign tumors of slow growth, but 40% of them present local invasion, a characteristic of behavior still unpredictable with the use of current tumor markers. This work aims to evaluate the tissue markers E-cadherin and NCAM, which act on cell adhesion, in tumor tissue samples of NFPA and its relationship with the degree of local invasiveness. Gene expression of E-cadherin (CDH1) and NCAM (NCAM1) was assessed by real-time PCR and tissue expression by immunohistochemistry. Fifty-three patients with macroadenomas were submitted to transsphenoidal surgery, presented grade II invasive adenomas in 16 cases (30.2%), grade III in 7 (13.2%) and grade IV in 30 (56.6%). In the immunohistochemistry, one case was negative for E-cadherin, 7 showed weak immunostaining, 17 moderate and 28 strong, whereas for NCAM, 5 showed negative, 28 weakly, 14 moderate and 6 strong. Regarding gene expression, 43.3% showed expression for CDH1 (mean of 2.12) and 50% for NCAM1 (mean of 1.86). There was no significant correlation between the immunohistochemical expression of the markers, as well as the gene expression, the degree of invasiveness and clinical data. The results suggest that E-cadherin and NCAM markers are not directly related to the invasiveness in NFPA.

PTTG overexpression in non-functioning pituitary adenomas: Correlation with invasiveness, female gender and younger age.

BACKGROUND: Non-functioning pituitary adenomas (NFPA) are prevalent pituitary neoplasms. Because they do not present with hormonal hypersecretion, there is no marker that indicates regrowth or recurrence, as in other adenomas. OBJECTIVES: Evaluate the immunohistochemical expression of PTTG, CD105 and Ki-67 and their relationships with age, gender, invasiveness, hormonal expression and regrowth or recurrence in the follow-up of NFPA operated and not submitted to radiotherapy. METHODS: Included 56 patients submitted to transsphenoidal surgery. Clinical data were obtained from medical records. The invasion degree was obtained by Hardy's classification. RESULTS: Mean age 55 ±â€¯13.6 years, 62.5% men and 68% invasive. Lesion persistence was present in 62.2% and regrowth in 35.7%. The recurrence-free survival rate was 94.5%, 75.4% and 69.1% (1, 2 and 3 years). No patient presented recurrence. The PTTG was positive in 55.3%, with statistically significant relationship with invasiveness, age and female gender, without relation to regrowth. The microvascular density showed statistically significant relationship with male gender, negative correlation with PTTG (r = -0.434, p = 0.001), and no relation with invasiveness and regrowth. The Ki-67 showed statistically significant relationship with age, tendency towards regrowth (p = 0.054) and, with no relation to invasiveness. CONCLUSIONS: It is suggested that PTTG can be used as a prognostic marker in NFPA.

[Morphofunctional features of non-functioning pituitary adenomas]. / Morfofunktsional'nye osobennosti gormonal'no-neaktivnykh adenom gipofiza.

Non-functioning pituitary adenomas (NFPAs) account for about 30% of all pituitary tumors. NFPAs are characterized by the lack of secretory potential or its weak expression insufficient for determination of the blood level of adenohypophyseal tropic hormones and for development of a specific clinical picture. Morphologically, NFPAs are a heterogeneous group of tumors, the classification of which was previously based only on immunoreactivity for pituitary tropic hormones. The WHO revised its Classification of Tumors of Endocrine Organs (4th edition) in 2017. The main changes relate to adenohypophysial-cell lineage for the designation of adenomas into subtypes. The introduction of transcription factor antibodies has become a fundamentally new approach to the classification of NFPAs, which is necessary to recognize less differentiated tumor types. This paper provides information on the new histopathological classification of pituitary adenomas, on the theories of silent adenomas, and on the proliferative and prognostic markers of NFPAs.

Non-invasive radiomics approach potentially predicts non-functioning pituitary adenomas subtypes before surgery.

PURPOSE: To make individualised preoperative prediction of non-functioning pituitary adenoma (NFPAs) subtypes between null cell adenomas (NCAs) and other subtypes using a radiomics approach. METHODS: We enrolled 112 patients (training set: n = 75; test set: n = 37) with complete T1-weighted magnetic resonance imaging (MRI) and contrast-enhanced T1-weighted MRI (CE-T1). A total of 1482 quantitative imaging features were extracted from T1 and CE-T1 images. Support vector machine trained a predictive model that was validated using a receiver operating characteristics (ROC) analysis on an independent test set. Moreover, a nomogram was constructed incorporating clinical characteristics and the radiomics signature for individual prediction. RESULTS: T1 image features yielded area under the curve (AUC) values of 0.8314 and 0.8042 for the training and test sets, respectively, while CE-T1 image features provided no additional contribution to the predictive model. The nomogram incorporating sex and the T1 radiomics signature yielded good calibration in the training and test sets (concordance index (CI) = 0.854 and 0.857, respectively). CONCLUSION: This study focused on the preoperative prediction of NFPA subtypes between NCAs and others using a radiomics approach. The developed model yielded good performance, indicating that radiomics had good potential for the preoperative diagnosis of NFPAs. KEY POINTS: • MRI may help in the pre-operative diagnosis of NFPAs subtypes • Retrospective study showed T1-weighted MRI more useful than CE-T1 in NCAs diagnosis • Treatment decision making becomes more individualised • Radiomics approach had potential for classification of NFPAs.

Mortality in patients with non-functioning pituitary adenoma.

Non-functioning pituitary adenomas (NFA) are benign pituitary neoplasms not associated with clinical evidence of hormonal hypersecretion. A substantial number of patients with NFA have morbidities related to the tumor and possible recurrence(s), as well as to the treatments offered. Studies assessing the long-term mortality of patients with NFA are limited. Based on the published literature of the last two decades, overall, the standardized mortality ratios in this group suggest mortality higher than that of the general population with deaths attributed mainly to circulatory, respiratory and infectious causes. Women seem to have higher mortality ratios, and assessment of time trends suggests improvement over the years. There is no consensus on predictive factors of mortality but those most consistently identified are older age at diagnosis and high doses of glucocorticoid substitution therapy. Well designed and of adequate power studies are needed to establish the significance of factors compromising the survival of patients with NFA and to facilitate improvements in long-term prognosis.

Management of non-functioning pituitary adenomas: surgery.

Non-functional pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that do not over-secrete hormonal products, therefore, they are generally detected through symptoms of mass effect, including headache, vision loss, or hypopituitarism. There are multiple pathological subtypes of NFPAs, such as null cell adenomas, silent gonadotrophs, silent somatotrophs, silent corticotrophs, and silent subtype 3, all of which can be classified based on immunohistochemical studies and electron microscopy. Despite these numerous pathological subtypes, surgical resection remains the first-line treatment for NFPAs. Diagnosis is best made using high resolution MRI brain with and without gadolinium contrast, which is also helpful in determining the extent of invasion of the tumor and recognizing necessary sinonasal anatomy prior to surgery. Additional pre-operative work-up should include full laboratory endocrine evaluation with replacement of hormone deficiencies, and ideally, full neuro-ophthalmologic exam. Although transcranial surgical approaches to the pituitary gland can be performed, the most common approach used is the transnasal transsphenoidal approach with endoscopic or microscopic visualization. This approach avoids retraction of the brain and cranial nerves during tumor removal. Surgery for symptoms caused by mass effect, including headaches and visual loss, are successfully treated with surgical resection, resulting in improvement in pre-operative symptoms as high as 90% in some reports. Although the risk of complications is low, major and minor events, such as permanent hypopituitarism, persistent CSF leak, and carotid artery injury can occur at rates ranging from zero to about 9%.

Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas.

PURPOSE: Non-functioning pituitary adenomas (NFPAs) are benign pituitary neoplasms that do not cause a hormonal hypersecretory syndrome. An improved understanding of their epidemiology, clinical presentation and diagnosis is needed. METHOD: A literature review was performed using Pubmed to identify research reports and clinical case series on NFPAs. RESULTS: They account for 14-54% of pituitary adenomas and have a prevalence of 7-41.3/100,000 population. Their standardized incidence rate is 0.65-2.34/100,000 and the peak occurence is from the fourth to the eighth decade. The clinical spectrum of NFPAs varies from being completely asymptomatic to causing significant hypothalamic/pituitary dysfunction and visual field compromise due to their large size. Most patients present with symptoms of mass effect, such as headaches, visual field defects, ophthalmoplegias, and hypopituitarism but also hyperprolactinaemia due to pituitary stalk deviation and less frequently pituitary apoplexy. Non-functioning pituitary incidentalomas are found on brain imaging performed for an unrelated reason. Diagnostic approach includes magnetic resonance imaging of the sellar region, laboratory evaluations, screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. CONCLUSION: This article reviews the epidemiology, clinical behaviour and diagnostic approach of non-functioning pituitary adenomas.

Malignant transformation in non-functioning pituitary adenomas (pituitary carcinoma).

Non-functioning pituitary carcinomas (NFPC) are defined as tumours of adenophyseal origin with craniospinal or systemic dissemination, with the absence of a hormonal hypersecretion syndrome. These are a histologically heterogenous group of tumours, comprising gonadotroph, null cell, "silent" tumours of corticotroph, somatotroph or lactotroph cell lineages as well as plurihormonal Pit-1 tumours. NFPC are exceedingly rare, and hence few cases have been described. This review has identified 38 patients with NFPC reported in the literature. Recurrent invasive non-functioning pituitary adenomas (NFPA) were observed in a majority of patients. Various factors have been identified as markers of the potential for aggressive behaviour, including rapid tumour growth, growth after radiotherapy, gain or shift of hormone secretion and raised proliferative markers. Typically, there is a latency of several years from the original presentation with an NFPA to identification of metastases and only 5 cases reported with rapidly progressive malignant disease within 1 month of presentation. Therapeutic options include debulking surgery, radiation therapy and chemotherapy with temozolomide recommended as first line systemic treatment. Although long-term survivors are described, prognosis remains generally very poor (median survival 8 months). Improvements in molecular tumour profiling may assist in predicting tumour behaviour, guide therapeutic choices and identify novel therapies.

Silent somatotroph pituitary adenomas: an update.

Silent growth hormone adenomas (SGHA) are a rare entity of non-functioning pituitary neuroendocrine tumors. Diagnosis is invariably made post-operatively of a tumor immunopositive for GH (and Pit-1 in selected cases) but without clinical acromegaly. Mainly young females are affected, and tumors are often uncovered by investigation for headaches or oligoamenorrhea. Integration of clinical, pathological and biochemical data is required for proper diagnosis. Beside normal IGF-1 levels, a third of SGHAs displays elevated GH levels and some will eventually progress to acromegaly. Almost two-thirds will be mixed GH-prolactin tumors and sparsely-granulated monohormonal GH tumors seems the more aggressive subtype. Recurrence and need for radiation is higher than other non-functioning tumors so close follow-up is warranted.

Pathogenesis of non-functioning pituitary adenomas.

The pathogenesis of non functioning pituitary adenomas (NFPA) is a complex process involving several factors, from molecular to genetic and epigenetic modifications, where tumor suppressor genes, oncogenes, cell cycle derangements have been demonstrated to play an important role. MicroRNAs (miRNAs) have also been identified as possible players in NFPA tumorigenesis and pituitary stem cells have been investigated for their potential role in pituitary tumor initiation. However, a critical role for paracrine signalling has also been highlighted. This review focuses on the current knowledge on the involvement of these factors in NFPA pathogenesis.

Post-operative imaging assessment of non-functioning pituitary adenomas.

BACKGROUND: Non-functioning pituitary adenomas (NFAs) are the most common pituitary tumors. There is significant variability in clinical practice in terms of post-operative imaging evaluation. The objective of this manuscript is to provide an exhaustive review of published articles pertaining to the post-operative imaging evaluation of NFAs. METHODS: The MEDLINE database was queried for studies investigating imaging for the post-operative evaluation of pituitary adenomas. From an initial search of 5589 articles, 37 articles were evaluated in detail and included in this review. RESULTS: Magnetic resonance imaging (MRI) is the gold standard for post-operative monitoring of NFAs, although functional imaging modalities may improve identification of residual tumor in conjunction with MRI. The residual tumor can be distinguished from post-operative changes by experienced practitioners using high-resolution MRI in the immediate post-operative setting (within 1 week of surgery). However, continued imaging evolution in the appearance of residual tumor or resection cavity is expected up to 3 months post-operatively. CONCLUSIONS: Post-operative imaging appearance of the pituitary gland, optic apparatus, and pneumocephalus patterns, correlated with the clinical outcomes. Long-term, lifetime follow-up is warranted for NFA patients who underwent surgical resection.

Integrative proteomics and transcriptomics identify novel invasive-related biomarkers of non-functioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) are usually macroadenomas and display invasion into surrounding tissues. The treatment for invasive NFPAs is still challenging. This study describes the differential patterns of gene expression between invasive and non-invasive NFPAs and identifies novel biomarkers involved in invasion of NFPAs for diagnosis and treatment. Using gene microarray technology, we examined the gene expression profile and found 1160 differentially expressed messenger RNA (mRNA) between invasive and non-invasive NFPAs. Then, we examined the protein profile by liquid chromatography tandem mass spectrometry (LC-MS/MS) and found 433 differentially expressed proteins between invasive and non-invasive NFPAs. Subsequently, we integrated the proteomics and transcriptomics datasets and identified 29 common changed molecules. Through bioinformatics analysis using Ingenuity Pathway Analysis (IPA) software, we showed that the 29 molecules were enriched in 25 canonical signaling pathways, 25 molecular and cellular functions, and 2 networks. Eight genes were identified involved in the invasion function by the molecular and cellular functions analysis, including CAT, CLU, CHGA, EZR, KRT8, LIMA1, SH3GLB2 and SLC2A1. Furthermore, we validated the decreased CHGA expression and increased CLU expression in invasive NFPAs by qRT-PCR and Western blot. Our study demonstrated that integration of proteomics and transcriptomics could prove advantageous for accelerating tumor biomarker discovery and CHGA and CLU might be important novel biomarkers and therapeutic targets for invasion of NFPAs.

Intraoperative magnetic resonance imaging assessment of non-functioning pituitary adenomas during transsphenoidal surgery.

PURPOSE: To review the utility of intraoperative imaging in facilitating maximal resection of non-functioning pituitary adenomas (NFAs). METHODS: We performed an exhaustive MEDLINE search, which yielded 5598 articles. Upon careful review of these studies, 31 were pertinent to the issue of interest. RESULTS: Nine studies examined whether intraoperative MRI (iMRI) findings correlated with the presence of residual tumor on MRI taken 3 months after surgical resection. All studies using iMRI of >0.15T showed a ≥90% concordance between iMRI and 3-month post-operative MRI findings. 24 studies (22 iMRI and 2 intraoperative CT) examined whether intraoperative imaging improved the surgeon's ability to achieve a more complete resection. The resections were carried out under microscopic magnification in 17 studies and under endoscopic visualization in 7 studies. All studies support the value of intraoperative imaging in this regard, with improved resection in 15-83% of patients. Two studies examined whether iMRI (≥0.3T) improved visualization of residual NFA when compared to endoscopic visualization. Both studies demonstrated the value of iMRI in this regard, particularly when the tumor is located lateral of the sella, in the cavernous sinus, and in the suprasellar space. CONCLUSION: The currently available literature supports the utility of intraoperative imaging in facilitating increased NFA resection, without compromising safety.

Microarray technology reveals potentially novel genes and pathways involved in non-functioning pituitary adenomas.

Microarray data of non-functioning pituitary adenomas (NFPAs) were analyzed to disclose novel genes and pathways involved in NFPA tumorigenesis. Raw microarray data were downloaded from Gene Expression Omnibus. Data pre-treatment and differential analysis were conducted using packages in R. Functional and pathway enrichment analyses were performed using package GOs-tats. A protein-protein interaction (PPI) network was constructed using server STRING and Cytoscape. Known genes involved in pituitary adenomas (PAs), were obtained from the Comparative Toxicogenomics Database. A total of 604 differentially expressed genes (DEGs) were identifed between NFPAs and controls, including 177 up- and 427 down-regulated genes. Jak-STAT and p53 signaling pathways were significantly enriched by DEGs. The PPI network of DEGs was constructed, containing 99 up- and 288 down-regulated known disease genes (e.g. EGFR and ESR1) as well as 16 up- and 17 down-regulated potential novel NFPAs-related genes (e.g. COL4A5, LHX3, MSN, and GHSR). Genes like COL4A5, LHX3, MSN, and GHSR and pathways such as p53 signaling and Jak-STAT signaling, might participate in NFPA development. Although further validations are required, these findings might provide guidance for future basic and therapy researches.