Genomic and molecular characterization of pituitary adenoma pathogenesis: review and translational opportunities

OBJECTIVEInnovations in genomics, epigenomics, and transcriptomics now lay the groundwork for therapeutic interventions against neoplastic disease. In the past 30 years, the molecular pathogenesis of pituitary adenomas has been characterized. This enhanced understanding of the biology of pituitary tumors has potential to impact current treatment paradigms, and there exists significant translational potential for these results. In this review the authors summarize the results of genomics and molecular biology investigations into pituitary adenoma pathogenesis and behavior and discuss opportunities to translate basic science findings into clinical benefit.METHODSThe authors searched the PubMed and MEDLINE databases by using combinations of the keywords “pituitary adenoma,” “genomics,” “pathogenesis,” and “epigenomics.” From the initial search, additional articles were individually evaluated and selected.RESULTSPituitary adenoma growth is primarily driven by unrestrained cell cycle progression, deregulation of growth and proliferation pathways, and abnormal epigenetic regulation of gene expression. These pathways may be amenable to therapeutic intervention. A significant number of studies have attempted to establish links between gene mutations and tumor progression, but a thorough mechanistic understanding remains elusive.CONCLUSIONSAlthough not currently a prominent aspect in the clinical management of pituitary adenomas, genomics and epigenomic studies may become essential in refining patient care and developing novel pharmacological agents. Future basic science investigations should aim at elucidating mechanistic understandings unique to each pituitary adenoma subtype, which will facilitate rational drug design.

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PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

Protein and Peptide Letters ◽

10.2174/0929866526666190722145449 ◽

2019 ◽

Vol 26 (11) ◽

pp. 800-818

Author(s):

Zujian Xiong ◽

Xuejun Li ◽

Qi Yang

Keyword(s):

Cell Cycle ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Cell Cycle Progression ◽

Key Factors ◽

Cycle Progression ◽

Sister Chromatids ◽

Regulation Of Cell Cycle ◽

Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

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MICROSURGICAL ANATOMY OF THE DIAPHRAGMA SELLAE AND ITS ROLE IN DIRECTING THE PATTERN OF GROWTH OF PITUITARY ADENOMAS

Neurosurgery ◽

10.1227/01.neu.0000317321.79106.37 ◽

2008 ◽

Vol 62 (3) ◽

pp. 717-723 ◽

Cited By ~ 39

Author(s):

Alvaro Campero ◽

Carolina Martins ◽

Alexandre Yasuda ◽

Albert L. Rhoton

Keyword(s):

Pituitary Adenoma ◽

Cavernous Sinus ◽

Dura Mater ◽

Pituitary Adenomas ◽

Potential Role ◽

Pituitary Tumors ◽

Microsurgical Anatomy ◽

Suprasellar Region ◽

Lateral Distance ◽

Diaphragma Sellae

Abstract OBJECTIVE To evaluate the anatomic aspects of the diaphragma sellae and its potential role in directing the growth of a pituitary adenoma. METHODS Twenty cadaveric heads were dissected and measurements were taken at the level of the diaphragma sellae. RESULTS The diaphragma sellae is composed of two layers of dura mater. There is a remarkable variation in the morphology of the diaphragm opening. The average anteroposterior distance of the opening was 7.26 mm (range, 3.4–10.7 mm) and the average lateral-to-lateral distance was 7.33 mm (range, 2.8–14.1 mm). CONCLUSION The variability in the diameter of the opening of the diaphragma sellae could explain the growth of pituitary tumors toward the cavernous sinus or toward the suprasellar region.

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Advances in Our Understanding of Pituitary Adenoma

US Endocrinology ◽

10.17925/use.2008.04.01.88 ◽

2008 ◽

Vol 04 (01) ◽

pp. 88

Author(s):

Sandra Pekic ◽

Vera Popovic-Brkic

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Pituitary Tumors ◽

Pituitary Hormones ◽

Current Treatment ◽

Thyroid Stimulating Hormone ◽

Treatment Modalities ◽

High Resolution Computed Tomography ◽

New Therapeutic Approaches ◽

Asymptomatic Patients

Pituitary adenomas are common benign monoclonal neoplasms— accounting for 15% of intracranial neoplasms—that may be clinically silent or secrete anterior pituitary hormones such as prolactin, growth hormone (GH), adrenocorticotrophic hormone (ACTH), or, rarely, thyroid-stimulating hormone (TSH) or gonadotrophins. Radiological studies for other reasons using high-resolution computed tomography (CT) or magnetic resonance imaging (MRI) detect incidental pituitary adenomas in approximately 20% of asymptomatic patients.1The incidence of the various types of adenoma varies;2prolactinomas are the most common pituitary adenomas. Clinically non-functioning pituitary adenomas (NFPAs), which do not secrete hormones, often cause local mass symptoms and represent one-third of pituitary adenomas. GH- and ACTH-producing adenomas each account for 10–15% of pituitary adenomas, while TSH-producing adenomas are rare. Pituitary adenomas are infrequent in childhood: fewer than 10% of pituitary adenomas are diagnosed before 20 years of age.3These adenomas can be either microor macroadenomas. The natural course of microadenomas is that a few tumors enlarge over a period of more than eight years.Although several genes and signaling pathways have been identified as important factors in the development of pituitary tumors, our understanding of pituitary tumorigenesis remains incomplete and is the focus of current research. The reason for this is that current treatment modalities fail to completely control this disorder and prevent the associated morbidity and mortality. This article reviews the advances in our understanding of pituitary adenoma, especially in the field of pathogenesis of pituitary tumors, and the possibility of new therapeutic approaches.

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High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas

Acta Endocrinologica ◽

10.1530/eje-11-0304 ◽

2011 ◽

Vol 165 (4) ◽

pp. 509-515 ◽

Cited By ~ 102

Author(s):

Maria A Tichomirowa ◽

Anne Barlier ◽

Adrian F Daly ◽

Marie-Lise Jaffrain-Rea ◽

Cristina Ronchi ◽

...

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Pediatric Patients ◽

Young Patients ◽

Gene Mutations ◽

Clinical Analysis ◽

Clinical Genetic ◽

Interacting Protein ◽

Aip Gene ◽

Pituitary Macroadenomas

BackgroundAryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.MethodsWe included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.ResultsOverall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.ConclusionGermline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

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Novel somatic variants involved in biochemical activity of pure growth hormone-secreting pituitary adenoma without GNAS variant

Scientific Reports ◽

10.1038/s41598-021-95829-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cheol Ryong Ku ◽

Hyeonseob Lim ◽

Yang Jong Lee ◽

Sun Ho Kim ◽

Daham Kim ◽

...

Keyword(s):

Growth Hormone ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Pituitary Tumors ◽

Genetic Alterations ◽

Biochemical Activity ◽

Recurrent Point ◽

Targeted Resequencing ◽

Severance Hospital

AbstractWe aimed to identify somatic genetic alterations in pure growth hormone (GH)-secreting pituitary adenomas without GNAS variants. Patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenomectomy at Severance Hospital, Yonsei University College of Medicine were recruited. Somatic genetic alterations were profiled by whole-exome sequencing (WES) and targeted resequencing. WES was performed using DNA from nine GH-secreting pituitary tumors and corresponding blood samples. Absence of GNAS variant was confirmed by Sanger sequencing. For targeted resequencing of 140 fixed tissues, 48 WES-derived candidate genes and 7 GH-secreting pituitary adenoma-associated genes were included. Forty-eight genes with 59 somatic variants were identified by WES. In targeted resequencing, variants in 26 recurrent genes, including MAST4, PRIM2, TNN, STARD9, DNAH11, DOCK4, GPR98, BCHE, DARS, CUBN, NGDN, PLXND1, UNC5B, and COL22A1, were identified, but variants in previously reported genes were not detected. BCHE, DARS, NGDN, and UNC5B variants were associated with increased GH-secreting pituitary tumor biochemical activity, which was confirmed in vitro. Although recurrent point variants were rare, several somatic variants were identified in sporadic pure GH-secreting pituitary adenomas. Several somatic variants may affect pathways involved in the tumorigenesis and biochemical activities of GH-secreting pituitary adenomas.

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Familial isolated pituitary adenoma syndrome

Orvosi Hetilap ◽

10.1556/oh.2011.29093 ◽

2011 ◽

Vol 152 (18) ◽

pp. 722-730 ◽

Cited By ~ 1

Author(s):

Judit Dénes ◽

Márta Korbonits ◽

Erika Hubina ◽

Gábor László Kovács ◽

László Kovács ◽

...

Keyword(s):

Pituitary Adenoma ◽

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Protein Gene ◽

Gene Mutations ◽

Carney Complex ◽

Incomplete Penetrance ◽

Causative Gene ◽

Interacting Protein ◽

Aryl Hydrocarbon

Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor. Orv. Hetil., 2011, 152, 722–730.

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Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas

BMC Endocrine Disorders ◽

10.1186/s12902-021-00720-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Farzad Izak Shirian ◽

Mohammad Ghorbani ◽

Mohammad E. Khamseh ◽

Mehrnaz Imani ◽

Mahshid Panahi ◽

...

Keyword(s):

Pituitary Adenoma ◽

Expression Pattern ◽

Protein Level ◽

Pituitary Adenomas ◽

Pituitary Tumors ◽

Expression Level ◽

Sox9 Expression ◽

Over Expression ◽

Tumor Tissues ◽

Sox9 Gene

Abstract Background Pituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated. Methods The SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient’s clinical and pathological features were considered. Results The SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors. Conclusion The study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.

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Pituitary adenoma in aged rats. A case report

Journal of the Hellenic Veterinary Medical Society ◽

10.12681/jhvms.14948 ◽

2018 ◽

Vol 59 (1) ◽

pp. 58

Author(s):

M KATSIMPOULAS ◽

M FOTEINOU ◽

E PARONIS ◽

P ALEXAKOS ◽

N KOSTOMITSOPOULOS

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Large Scale ◽

Laboratory Animals ◽

Neoplastic Disease ◽

Aged Rats ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Neoplastic Lesion ◽

Toxicological Studies

The prevalence of neoplastic disease in the rat is well defined, because this species has been routinely used for decades in large-scale carcinogenic, aging and toxicological studies. Stock and strain-specific differences in the prevalence of some types of tumors are well documented. Pituitary adenoma is a neoplastic lesion which can be observed in older or aged rats of both sexes. In addition to sex, strain, diet, genetic factor, breeding history and accommodation may also play a role. Pituitary adenoma can also affect hamster, guinea pig and mice. The aim of this article is to report an incidence of pituitary adenomas, which was observed in a rat breeding colony of the Center for Experimental Surgery of the Biomedical Research Foundation of the Academy of Athens. During the clinical examination five female Wistar rats, at the age of 18 to 24 months old, expressed anorexia, weight loss, ataxia and bilateral blindness. At necropsy, the pituitary gland was enlarged with lobulations, often dark red to brown and hemorrhagic in appearance. In some cases there was a marked compression of the overlying mesencephalon. Histological examination with haematoxylin-eosin were observed cords and nests of glandular cells bound by strands of connective tissue, with an abundant capillary network. On immunohistochemical examination were observed strong positive reaction of synaptophysin. Findings were similar to pituitary adenoma. Pituitary adenoma is a serious non-reversible disease leading to the death of the animal. Laboratory animals with pituitary adenomas can be used as models in research of human pituitary adenoma.

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Reformatted Sagittal Images in the Differential Diagnosis of Meningiomas and Pituitary Adenomas with Suprasellar Extension

Neurosurgery ◽

10.1227/00006123-198605000-00007 ◽

1986 ◽

Vol 18 (5) ◽

pp. 555-558 ◽

Cited By ~ 8

Author(s):

Craig W. Clark ◽

James D. Acker ◽

Jon H. Robertson ◽

Frank Eggers ◽

Michael S. Muhlbauer

Keyword(s):

Computed Tomography ◽

Differential Diagnosis ◽

Pituitary Adenoma ◽

High Resolution ◽

Pituitary Adenomas ◽

Pituitary Tumors ◽

Suprasellar Extension

Abstract Approximately 3 to 4 times a year, a tumor with suprasellar extension escapes classification on high resolution coronal and transaxial computed tomography. When arteriography failed to determine the diagnosis, the differential choices were usually meningioma or pituitary adenoma. The authors report the use of sagittal reformatted images in this differential diagnosis and conclude that these images may aid in the distinction between pituitary tumors with suprasellar extension and meningiomas located in this area.

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Aryl Hydrocarbon Receptor-Interacting Protein Gene Mutations in Familial Isolated Pituitary Adenomas: Analysis in 73 Families

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2513 ◽

2007 ◽

Vol 92 (5) ◽

pp. 1891-1896 ◽

Cited By ~ 192

Author(s):

Adrian F. Daly ◽

Jean-François Vanbellinghen ◽

Sok Kean Khoo ◽

Marie-Lise Jaffrain-Rea ◽

Luciana A. Naves ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Outcome Measures ◽

Pituitary Adenomas ◽

Collaborative Study ◽

Gene Mutations ◽

Pituitary Tumors ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Aip Gene ◽

The Impact

Abstract Context: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. Objective: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). Design: This was a multicenter, international, collaborative study. Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries. Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures. Intervention: There was no intervention. Results: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

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