Molecular genetic advances in pituitary tumor development

Abstract

Pituitary adenomas are a heterogeneous group of tumors that may occur as part of a complex syndrome or as an isolated endocrinopathy and both forms can be familial or non-familial. Studies of syndromic and non-syndromic pituitary adenomas have yielded important insights about the molecular mechanisms underlying tumorigenesis. Thus, syndromic forms, including multiple endocrine neoplasia type 1 (MEN1), MEN4, Carney Complex and McCune Albright syndrome, have been shown to be due to mutations of the tumor-suppressor protein menin, a cyclin-dependent kinase inhibitor (p27^Kip1), the protein kinase A regulatory subunit 1-α, and the G-protein α-stimulatory subunit (Gsα), respectively. Non-syndromic forms, which include familial isolated pituitary adenoma (FIPA) and sporadic tumors, have been shown to be due to abnormalities of: the aryl hydrocarbon receptor-interacting protein; Gsα; signal transducers; cell cycle regulators; transcriptional modulators and miRNAs. The roles of these molecular abnormalities and epigenetic mechanisms in pituitary tumorigenesis, and their therapeutic implications are reviewed.

Keywords:

• epigenetics
• genetic syndromes
• miRNA
• molecular genetics
• pituitary adenoma
• therapy

Financial & competing interests disclosure

This work was supported by the: United Kingdom Medical Research Council (MRC) programme grants (G9825289 and G1000467 to KE Lines and RV Thakker); National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (to KE Lines and RV Thakker); Royal Australasian College of Physicians Vincent Fairfax Family Foundation Research Fellowship (to CJ Yates); Australia Awards Endeavour Postgraduate Research Fellowship Award (to CJ Yates); Novartis Pharmaceuticals Australia Educational Grant (to CJ Yates); Ipsen Pharmaceuticals Australia Educational Grant (to CJ Yates) and The Unicorn Foundation Educational Grant (to CJ Yates). RV Thakker is a member of an ad hoc panel for Novartis (fees paid to institution); has received lecture fees at a sponsored conference from Novartis, Ipsen, Novo Nordisk and Eli Lilly (fees paid to institution) and is Chairman of AstraZeneca advisory group (fees paid to institution). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Mutations occurring in syndromic forms of pituitary tumors (∼5% of all pituitary adenomas) are rarely observed in patients with non-syndromic pituitary tumors, with the exception of GNAS1 (gsp) mutations, which are found in approximately 30–40% of somatotrophinomas.

• Approximately 95% of pituitary adenomas occur as non-familial sporadic tumors, yet have genetic and epigenetic abnormalities, which involve cell cycle regulators, signal transducers, transcriptional modulators and cytokines.

• Epigenetic changes, including methylation-induced transcriptional silencing, frequently influence sporadic pituitary adenoma development.

• miRNAs post-transcriptionally regulate gene expression and sporadic pituitary adenoma subtypes may exhibit specific miRNA expression profiles.

• Targeted medical therapy with dopamine agonists and somatostatin analogs are effective for many pituitary adenomas. However, future novel agents targeting EGFR, VEGF, miRNA, gene replacement and cyclin-dependent kinases may help in treating aggressive pituitary adenomas and pituitary carcinomas.

Notes