Genetic and Epigenetic Causes of Pituitary Adenomas

Abstract

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel-Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

Keywords: Cushing’s disease; acromegaly; molecular markers; non-secreting adenomas; pituitary adenomas.

Figure 1

Tumorigenic mechanisms in somatotroph cells. Several mechanisms increase cAMP production, which is key for somatotroph tumorigenesis. Hormones bind to receptors, including GHRH-R, SSTR, GPR101, and GIPR, on the somatotroph cell membrane and increase the activation of adenylyl cyclase through Gsα. The consequent increase in cAMP production leads to the dissociation of the regulatory subunits of PKA from the catalytic subunits, which then translocate to phosphorylate CREB in the nucleus and other targets, leading to increased GH expression and cell proliferation. Gsα activation induced by GNAS mutations also leads to upregulation of the cAMP pathway. In addition, ectopic expression of GIPR may lead to an activated cAMP pathway, and GPR101 is a Gsα-coupled constitutively active receptor that leads to increased cAMP signaling. AIP, aryl hydrocarbon receptor-interacting protein; ATP, adenosine triphosphate; C, catalytic subunit; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element; GHRH, growth hormone-releasing hormone; GHRH-R, GHRH receptor; GIPR, gastric inhibitory polypeptide receptor; GPR101, G protein-coupled receptor 101; Gsα, G protein stimulatory alpha subunit; GTP, guanine triphosphate; PKA, protein kinase A; R, regulatory subunit; SSTR, somatostatin receptor; ZAC1, zinc finger protein PLAGL1.

Figure 2

Tumorigenic mechanisms in corticotroph cells. USP8 removes ubiquitin tags from targets, such as EGFR and Smoothened (SMO), preventing them from undergoing proteasomal degradation and allowing recycling back to the cell surface. Increased EGFR and SMO activity leads to increased cAMP and POMC levels. Mutated USP8 cannot bind 14-3-3 protein and undergoes cleavage, which increase enzymatic activity, leading to increased deubiquitination of EGFR and SMO and higher expression of the two proteins on the cell membrane. USP48 mutations and gain-of-function mutations of BRAF probably play a similar role to USP8.