Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Abstract

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis.

Keywords: PitNET; pituitary adenoma; pituitary neoplasm; pituitary tumor; pituitary tumorigenesis.

Graphical Abstract

Figure 1.

Genetic and epigenetic mechanisms of pituitary tumorigenesis. Genetic mechanisms may be secondary to germline or somatic mutations, while epigenetic mechanisms can be mediated at the chromatin level (such as in the case of DNA methylation or histone modifications) or via noncoding RNAs.

Figure 2.

Germline or mosaic mutations causing pituitary tumors. Pituitary tumors presenting in isolation (familial isolated pituitary adenoma, FIPA) or part of a tumor syndrome. Hyperplasia has been described in Carney complex, McCune-Albright syndrome, 20% of XLAG cases and rarely in AIP mutation positive cases. Genes marked with red letter types are oncogenes, while the black ones are tumor suppressor genes. Abbreviations: G, germline; GIST, gastrointestinal stromal tumor; HPGL, hereditary paraganglioma; LCCSCT, large-cell calcifying Sertoli cell tumors; M, mosaic; NET, neuroendocrine tumor; pHPT, primary hyperparathyroidism; PPB, pleuropulmonary blastoma; RCC, renal cell carcinoma; S, somatic; SLCT, Sertoli–Leydig cell tumor.

Figure 3.

Tumorigenic mechanism in somatotroph cells. cAMP-associated pathways are key for somatotroph tumorigenesis. GHRH released by the hypothalamus interacts with its receptor (GHRH-R) on the somatotroph cell membrane to increase activation of adenylyl cyclase through Gαs. Consequent increased cAMP production leads to the dissociation of the regulatory subunits (R) of protein kinase A (PKA) from the catalytic subunits (C), which then translocate to the nucleus and phosphorylate CREB (cAMP response element) and other targets, eventually leading to increased GH expression and cell proliferation. Mosaic (McCune-Albright syndrome) or somatic activating mutations in GNAS (coding for Gαs) lead to upregulation of the cAMP pathway. In Carney complex, increased PKA activity, either due to the inhibitory action of the regulatory subunit PRKAR1A, or increased catalytic subunit activity (PRKACB) leads to tumorigenesis. Loss of AIP has been shown to increase cAMP signaling through (1) decreased expression of the G inhibitory protein Gαi-2, which mediates the inhibitory effects of somatostatin (SS) on adenylyl cyclase. AIP deficiency is associated with reduced Gαi-2 expression in human and mouse GH-PTs (2, 32) an interaction with phosphodiesterases type 4 (PDE4) (36); expression of type 4 phosphodiesterase is lower in AIP-mutated GH-PTs compared to sporadic GH-PTs (37) and AIP mutations disrupt the interaction of AIP with PDE4A5 in GH3 cell (3, 35) interaction of AIP with members of the PKA complex (38, 39). AIP deficiency results in reduced ZAC1 levels (40, 41) and is associated with mitochondrial proteins TOMM20 and HSPA9 (39, 69), the endoplasmatic reticulum calcium channel RYR (31) and with secretory vesicles (35), but the exact mechanisms as to how these interactions might lead to tumorigenesis are unclear. GPR101 is Gsα-coupled constitutively active receptor leading to increased cAMP signaling. The mechanism of GPR101-related tumorigenesis may occur via a dual mechanism: hypothalamic dysregulation as elevated GHRH levels can be measured in some patients, while there may be a direct pituitary action due to increased GPR101 expression on pituitary cells. Recently an endogenous ligand has been identified, the lipid mediator Resolvin D5 (RvD5), the role of this mediator in the regulation of the GH axis and its levels in patients with XLAG is currently unknown. Ectopic expression of GIPR may also lead to an activated cAMP pathway (70–72).

Figure 4.

Tumorigenic mechanism in corticotroph cells (154). USP8 removes ubiquitin tags through its deubiquitinase action from its targets, such as EGFR and smoothened (SMO), preventing them from being degraded in the lysosome and allowing recycling back to the cell surface. Increased EGFR and SMO activity leads to increased cAMP signaling and POMC levels. Mutated USP8 cannot bind 14-3-3 protein and undergoes cleavage, which increases its enzymatic activity, leading to increased deubiquitination of EGFR and SMO with higher expression on the cell membrane. Similarly, GLI1 and histone 2a (H2A) are suggested to be target of USP48 leading to increased activity with USP48 mutations. Loss-of-function of DICER1, TP53, MLH1 and MSH2 and gain-of-function of BRAF has also been suggested to be associated with corticotroph tumorigenesis.