Fendo 11 596554 1

REVIEW
published: 26 January 2021

doi: 10.3389/fendo.2020.596554
Genetic and Epigenetic Causes

of Pituitary Adenomas
Mengqi Chang †, Chengxian Yang †, Xinjie Bao * and Renzhi Wang *
Department of Neurosurgery, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Peking Union
Medical College & Chinese Academy of Medical Sciences, Beijing, China
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
Edited by:
syndromes. PAs have also been described in association with succinate dehydrogenase-
Hidenori Fukuoka,
Kobe University, Japan related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch
Reviewed by: syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations
Hiroshi Nishioka, often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast,
Toranomon Hospital, Japan
Murat Aydin Sav, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled
Yeditepe University, Turkey receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the
*Correspondence: deubiquitinase gene USP8, USP48, and BRAF mutations are associated with
Xinjie Bao
adrenocorticotropic hormone production. In this review, we describe the genetic and
[email protected]
Renzhi Wang epigenetic landscape of PAs and summarize novel insights into the regulation of
[email protected] pituitary tumorigenesis.
†
These authors have contributed
equally to this work Keywords: pituitary adenomas, molecular markers, acromegaly, Cushing’s disease, non-secreting adenomas
Specialty section:
This article was submitted to
Pituitary Endocrinology,
INTRODUCTION
a section of the journal
Pituitary adenomas (PAs) are the second most common brain tumors, accounting for
Frontiers in Endocrinology
approximately 15% of all primary brain tumors (1). PAs can be classified based on the types of
Received: 19 August 2020
hormones that they excessively secrete into the blood. The clinical presentations caused by hormone
Accepted: 23 November 2020
overproduction in PAs are closely related to the pituitary cell types, as follows: corticotropin-secreting
Published: 26 January 2021
corticotroph adenomas result in Cushing’s disease, growth hormone (GH)-secreting somatotroph
Citation:
adenomas result in acromegaly, prolactin-secreting lactotroph adenomas result in hyperprolactinemia,
Chang M, Yang C, Bao X and Wang R
(2021) Genetic and Epigenetic Causes
and thyrotropin-secreting thyrotroph adenomas result in hyperthyroidism (2). Non-secreting
of Pituitary Adenomas. adenomas, such as null cell adenomas, silent gonadotroph adenomas, silent corticotroph adenomas,
Front. Endocrinol. 11:596554. and silent somatotroph adenomas, lead to hypogonadism and often manifest as incidental sellar
doi: 10.3389/fendo.2020.596554 masses (2). Of the different PA types, only lactotroph adenomas are treated with dopamine agonists as
Frontiers in Endocrinology | www.frontiersin.org 1 January 2021 | Volume 11 | Article 596554

Chang et al. Pituitary Tumorgenesis Mechanism
a first-line option. Because of a lack of effective drugs, other PA mutations likely lead to PAs by influencing cell cycle regulation.
subtypes are generally treated with transsphenoidal surgery as the
first-line therapy (3). Furthermore, because many PAs are invasive Carney Complex
and unresectable—or in some cases of Cushing’s disease, because Carney complex is characterized by endocrine and non-
the tumors themselves are too small to be detected or completely endocrine tumors with spotty skin pigmentation, as well as by
removed during surgery—drugs and stereotactic radiosurgery are cardiac and cutaneous myxomas (18). More than two-thirds of
needed to achieve tumor control or biochemical remission. patients present asymptomatic elevations of insulin-like growth
However, despite current treatments, the 10-year recurrence rate factor 1 (IGF-1), GH, and prolactin caused by pituitary
remains as high as 7–12% (3, 4). It is therefore important to obtain hyperplasia, and 10% of patients present with adenomas and
a comprehensive understanding of the molecular biological symptomatic acromegaly (19). In some cases, Carney complex is
characteristics of different types of PAs, such as gene mutations, caused by an inactivating mutation of the PRKAR1A gene, which
DNA methylation, microRNA (miRNA) regulation, and encodes the type 1-alpha regulatory subunit of protein kinase A
regulation at other levels, to allow the targeted treatment of (20). In addition, a gain-of-function mutation has been described
individuals, thus achieving better prognoses. Herein, we in the gene encoding the catalytic subunit of protein kinase A,
summarize the known variation in the different types of PAs PRKACB (21).
and review the potential molecular targets for future
clinical application. X-LAG Syndrome
X-LAG syndrome is a newly defined syndrome in patients with
pituitary gigantism or PA who carry microduplications on
chromosome Xq26.3 (22, 23). X-LAG syndrome is generally
SYNDROMIC PITUITARY ADENOMA- recognized as an aggressive disease because it is difficult to control
RELATED VARIATIONS the excess GH. Most patients require multiple interventions (both
surgical and medical), and subtotal or total hypophysectomy is
Familial PAs can be divided into two types: isolated and sometimes necessary. In contrast, radiation therapy is not usually
syndromic (5). These familial PAs and their molecular helpful. X-LAG syndrome is probably caused by G protein-coupled
mechanisms are described herein. receptor 101 (GPR101) overexpression because the GPR101 gene is
located on chromosome Xq26.3. GPR101 is coupled to the
Multiple Endocrine Neoplasia stimulatory G protein complex and activates adenylate cyclase,
Type 1 Syndrome increasing cyclic adenosine monophosphate (cAMP) production.
MEN1 syndrome is classically characterized by the combined In addition, GPR101 amplification has also been identified as a
occurrence of parathyroid adenomas, PAs (in approximately 30– germline or mosaic mutation (22).
40% of cases), and neuroendocrine tumors (6). PAs that develop in
MEN1 syndrome include lactotroph adenomas (42–62%), silent Succinate Dehydrogenase-Related
PAs (15–42%), somatotroph adenomas (6.5–9%), and corticotroph Familial Pituitary Adenoma
adenomas (3–4%). In addition, somatic mutations in MEN1 can T h i s “ 3 P A s ” s y nd r o m e , w h ic h c o m b i ne s P A w it h
also be found in sporadic PAs (7). The MEN1 gene is located on pheochromocytoma/paraganglioma (PPGL), is sometimes
chromosome 11q13.1 and encodes a ubiquitously expressed associated with mutations in PPGL-predisposing genes, such as the
transcription cofactor of cyclins; MEN1 also participates in G1/S genes encoding SDHx (24, 25). Such mutations occur in SDHA-D
checkpoint regulation (8, 9). Approximately 10% of all MEN1- and SDHA2F, among others (24–28). SDH is a multimeric enzyme
related PA cases can be attributed to de novo mutations, which are that binds to the inner membranes of mitochondria. It has a dual role:
sometimes identified as a mosaicism in the proband (10, 11). it serves both as a critical step of the tricarboxylic acid or Krebs cycle,
and as a member of the respiratory chain that transfers electrons
Multiple Endocrine Neoplasia directly to the ubiquinone pool (25, 27, 29). Pituitary hyperplasia has
Type 4 Syndrome been reported to develop in a Sdhb-knockout mouse model (25).
Some patients with MEN1 syndrome harbor no MEN1 mutation.
Instead, cyclin-dependent kinase inhibitor 1B (CDKN1B) Neurofibromatosis Type 1 Syndrome
mutations have been detected in these patients. This syndrome Rarely, optic pathway gliomas cause high GH levels in NF1,
is known as MEN4 syndrome (12). Patients with MEN4 while true PAs are extremely rare. Empty sella syndrome and
syndrome are prone to developing somatotroph adenomas, hypopituitarism may also occur in the context of NF1. Lifelong
and can also develop other types of Pas (13). CDKN1B endocrine follow-up is recommended for all NF1 patients (13). A
mutations are rarely found in sporadic pituitary tumors (14, recent case report described a patient with a heterozygous
15). CDKN1B encodes a cyclin-dependent kinase inhibitor that guanine nucleotide-binding protein G(s) subunit alpha (GNAS)
regulates the cell cycle and mitosis from the G1 to the S phase R201C mutation in a somatotroph adenoma. This was the first
(13). CDKN1B-knockout mice develop various types of tumors, reported rare MEN1-like case of genetically diagnosed NF1
including PAs, and this tumorigenesis is associated with complicated with acromegaly caused by somatotroph
accelerated pituitary cell proliferation (16, 17). CDKN1B adenoma (14).

Von Hippel–Lindau Syndrome Genetic Variations

VHL syndrome is a heritable multisystem cancer syndrome that Somatotroph adenomas have greater genomic disruption than
is caused by germline mutations of the VHL tumor suppressor corticotroph adenomas or inactive tumors with no clinical
gene. The incidence of this disorder is as high as 1 in 36,000 live evidence of hormone secretion (38). Gene mutations in PAs
births (15). Patients with VHL syndrome are at risk of can be divided into heritable germline variations, mosaic
developing various benign and malignant tumors of the central mutations, and non-heritable somatic mutations (29). The
nervous system [i.e., pituitary stalk hemangioblastomas (15)], former two are often familial and associated with syndromes,
kidneys, adrenal glands, pancreas, and reproductive adnexal while the latter are sporadic (29). Mutations in aryl hydrocarbon
organs (16). It has been reported that propranolol can decrease receptor-interacting protein (AIP), GNAS, and cadherin-related
the viability of VHL-related hemangioblastomas and renal cell 23 (CDH23), which are all involved in cAMP-associated
carcinomas in vitro, likely by modulating vascular endothelial pathways, are key for somatotroph tumorigenesis (Figure 1,
growth factor expression and inducing apoptosis (17). However, Table 1).
propranolol treatment for this disease is limited to early
clinical trials. Aryl Hydrocarbon Receptor-Interacting Protein
Familial isolated pituitary adenoma (FIPA) is characterized by
DICER1 Syndrome the familial occurrence of PAs in the absence of other clinical
DICER1 syndrome is caused by heterozygous germline features (39). Germline mutations in the AIP gene are detected in
mutations in the DICER1 gene (30). Several cases have been approximately 20% of FIPA families and 50% of familial
reported of rare infantile-onset pituitary blastoma that were acromegaly families (40–43). AIP is located on human
mainly caused by germline mutations in DICER1 (31). chromosome 11q13.2, and acts as a tumor suppressor in PAs
Recently, corticotroph adenomas have also been identified in (44). Mutations in AIP have been identified as causing a
this tumor syndrome (31). DICER1 encodes a cytoplasmic predisposition for PAs of variable penetrance in 20% of FIPA
endoribonuclease that processes hairpin precursor miRNAs families (41). AIP mutations are usually associated with
into short, functional miRNAs that downregulate targeted somatotropinomas, but prolactinomas, non-functioning PAs
mRNAs, thereby modulating cellular protein production (32). (NF-PAs), Cushing’s disease, and other infrequent clinical
In addition, specific somatic mutations in the DICER1 RNase III adenoma types can also occur (40–43). AIP mutations are
catalytic domain have been identified in several DICER1- common in male pediatric acrogigantism patients, and tend to
associated tumor types (31, 33). cause large and invasive tumors; densely granulated subtypes
rarely occur, and patients with AIP mutations are often resistant
Lynch Syndrome to somatostatin analogue (SSA) treatment (42, 43, 45, 46).
Lynch syndrome is a cancer-predisposing syndrome caused by Families with AIP mutations show incomplete penetrance, of
germline mutations in genes involved in DNA mismatch repair approximately 15–30% (40, 42, 47). Genetic screening can
(34). Germline mutations in MLH1 (35) and MSH2 (34) in the identify carrier family members, and clinical screening has
mismatch repair pathway, have been identified in Lynch been reported to result in the earlier recognition of clinically
syndrome patients with aggressive corticotropin-secreting relevant disease in approximately 20% of patients (22/187) (43).
adenomas, although these are isolated case reports. Missense Mechanically, some of the mutations lead to truncation of the
mutations have also been detected in four mismatch repair genes AIP protein and loss of the C-terminal sequence, which affects
(MSH5, MSH6, MLH1, and MLH3) in non-secreting protein interactions and leads to disrupted AIP function. A
adenomas (3). number of mechanisms may explain the resistance of AIP-
mutated patients to SSAs. First, one mechanism may involve
the reduced expression of the inhibitory G protein subtype, Gai-
SOMATOTROPH ADENOMAS 2, which mediates the inhibitory effects of SSAs (44). Second, AIP
has been reported to interact with both phosphodiesterase
The incidence of somatotroph adenomas is approximately 10 cases (PDE) and guanine nucleotide-binding proteins (G proteins);
per 1 million individuals (2, 36, 37). Somatotroph adenomas are PDE4 expression is lower in AIP-mutated PAs, and interactions
GH-secreting somatotropic tumors that exhibit excessive secretion between PDE4 and AIP are disrupted by such mutations (44, 48,
of GH and IGF-1, causing acromegaly and abnormal growth of 49). Consistent with these findings, both PDE isoforms are
bones, tissues, and organs in patients. Currently, treatment methods reportedly overexpressed in GH cells from sporadic AIP
are limited to surgery, radiotherapy, somatostatin receptor (SSTR) mutation-negative GH-secreting adenomas (49). Third,
ligands, and GH receptor antagonists. Each of these treatments has AIP interacts with the protein kinase A (PKA) complex. AIP
specific side effects, and the efficacy varies greatly among different mutations affect the PKA pathway, thus affecting cell
patients; thus, it is hard to directly target and inhibit the continuous proliferation and development and the inflammatory response
secretion of GH in postoperative patients (2). It is necessary to (42, 49). Fourth, another mechanism of SSA resistance may be
further understand the molecular mechanisms of somatotroph related to the SSTR2–zinc-finger protein 1 PLAGL1 (ZAC1)
adenomas to elucidate new therapeutic targets. pathway (50). AIP is upregulated by SSAs, and AIP can in turn

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 Gsa. 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. Gsa 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 Gsa-
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; Gsa, G protein stimulatory alpha subunit; GTP, guanine triphosphate; PKA,
protein kinase A; R, regulatory subunit; SSTR, somatostatin receptor; ZAC1, zinc finger protein PLAGL1.
TABLE 1 | Genes affected in different pituitary tumors via genetic mutation or DNA methylation.
Gene (symbol) Gene name Location Function of gene product and mechanism of Tumor types associated with each
tumorigenesis genetic defect
MEN1 Multiple Endocrine Neoplasia 11q13.1 Tumor suppressor; Involved in cell proliferation, genome Lactotroph adenomas, somatotroph
type 1 stability and gene transcription adenoma, corticotroph adenomas, and
nonsecreting adenomas
CDKN1B cyclin-dependent kinase 12p13.1 Cell cycle regulation Prone to developing somatotroph
inhibitor 1B adenomas, and can also develop other
types of PAs
PRKAR1A Protein Kinase CAMP- 17q24.2 Loss of PRKAR1A causes enhanced PKA signaling. Somatotroph adenomas and lactotroph
Dependent Type I Regulatory adenomas
Subunit Alpha
GPR101 G-protein-coupled receptor Xq26.3 G-protein-coupled receptor; defects lead to constitutive Somatotroph adenomas
gene activation of the cAMP-PKA pathway
SDHx Succinate dehydrogenase x / Unknown More likely to produce prolactin; pituitary
hyperplasia in mice
VHL Von Hippel–Lindau 3p25.3 likely by modulating vascular endothelial growth factor Pituitary stalk hemangioblastomas
expression and inducing apoptosis
DICER Dicer 1, Ribonuclease III 14q32 Unknown Pituitary blastoma
MLH1 MutL Homolog 1 3p22.2 Unknown Corticotroph adenomas
MSH2 MutS Homolog 2 2p21 Unknown Corticotroph adenomas
AIP Aryl hydrocarbon receptor 11q13.2 Interaction in cAMP synthesis All types
interacting protein
(Continued)

TABLE 1 | Continued
GNAS Guanine nucleotide activating 20q13.32 cAMP-regulating protein Gsa; activation leads to increased Mainly in somatotroph adenomas
subunit cAMP levels and activation of protein kinase A (PKA)
PTTG1 Pituitary tumor-transforming 5q33.3 Enhanced PTTG1 is a regulator of sister chromatid All types
gene-1 segregation, this may subsequently drive chromosomal
instability
STAT3 Signal Transducer and 17q21.2 Enhanced STAT3 increased GH transcription. Somatotroph adenomas
Activator of Transcription 3
CDH23 Cadherin related 23 10q22.1 Calcium-dependent cell-cell adhesion glycoprotein Somatotroph adenomas account for the
highest proportion
IGSF1 Immunoglobulin superfamily Xq26.1 IGSF1 mutation weakens its transport to the cell surface in Hyperplasia with increased total GH
member 1 allogenic cells and increased total GH secretion and IGF-1 secretion and IGF-1 levels
levels
SLC20A1 Solute Carrier Family 20 2q14.1 Increased expression of SLC20A1 may be associated with Somatotroph adenomas
Member 1 the activation of the Wnt/b-catenin signaling pathway
PRDM2 PR/SET Domain 2 1p36.21 The absence of PRDM2 involved the tumorigenesis through Somatotroph adenomas
regulating c-Myc
SSTRs and DRDs Somatostatin receptors / Decreased expression of receptors (DRD4, DRD5, SSTR1 Somatotroph adenomas and silent
(SSTR1-5) and dopamine and SSTR2) may be associated with poor response to somatotroph adenomas
receptors (DRD1-5) SSAs
IGSF1 Immunoglobulin Superfamily Xq26.2 Membrane glycoprotein with modified residue possibly Hyperplasia, and sometimes with GH
Member 1 altering interaction with an extracellular ligand secretion and IGF-1 level increasing
SLC20A1 Solute Carrier Family 20 2q14.1 Increased SLC20A1 expression may be associated with Somatotroph adenomas
Member 1 activation of the Wnt–b-catenin signaling pathway
PRDM2 PR domain zinc finger protein 1p36.21 c-Myc regulation Somatotroph adenomas
2
GADD45g Growth Arrest and DNA 9q22.2 Tumor suppressor; Involved in DNA damage and function in Non-secreting adenomas and
Damage Inducible Gamma the negative regulation of cell growth somatotroph adenomas
LGALS3 Galectin 3 14q22.3 Promoter methylation status of LGALS3 for the regulation of Lactotroph adenomas, corticotroph
Gal-3 expression in PA adenomas
RASSF1A Ras Association Domain 3p21.31 Promoter methylation of RASSF1A is detected in all types of All types
Family Member 1 PAs and mechanism is unknown,
USP8 Ubiquitin Specific Peptidase 8 15q21.2 Involved in deubiquitination of EGFR; gain of functions Corticotroph adenomas
mutations results in increased EGFR, and POMC expression
USP48 Ubiquitin Specific Peptidase 1p36.12 Deubiquitination; activation of MAPK and increased POMC Corticotroph adenomas
48 expression
BRAF B-Raf Proto-Oncogene, 7q34 Proto-oncogene with tyrosine kinase activity; activation of Corticotroph adenomas
Serine/Threonine Kinase MAPK and increased POMC expression
USP90 Heat Shock Protein 90 / Unknown Corticotroph adenomas
HDAC2 histone deacetylase 2 6q21 Unknown Corticotroph adenomas
CABLES1 Cdk5 And Abl Enzyme 18q11 Unknown Corticotroph adenomas
Substrate 1
SFRP2 Secreted Frizzled-Related 4q31.3 overexpression of SFRP2 in AtT20 cells reduces b-catenin Corticotroph adenomas
Protein 2 levels in the cytoplasm and nucleus, and also decreases
Wnt signaling activity
POMC Proopiomelanocortin 2p23.3 Unknown Corticotroph adenomas
FGFR2 Fibroblast Growth Factor 10q26.13 Inducing Rb phosphorylation and regulation of cell cycle Corticotroph adenomas
Receptor 2 progression by p21 and p27
PTAG Pituitary Tumor Apoptosis 22q12.2 Unknown Corticotroph adenomas
Gene
TSP-1 Thrombospondin-1 15q14 Unknown Corticotroph adenomas
CASP-8 Caspase-8 2q33.1 Unknown Corticotroph adenomas
CABLES1 Cdk5 And Abl Enzyme 18q11 Unknown Corticotroph adenomas
Substrate 1
C5orf66-AS1 C5orf66 Antisense RNA 1 5q31.1 Unknown Pituitary null cell adenomas
IL-6R, JAK2, Interleukin 6 receptor/Janus / Unknown Pituitary null cell adenomas
STAT3, p-STAT3, kinase 2/STAT3/matrix
and MMP9 metallopeptidase 9
PI3K Phosphatidylinositol 3- 3q26.32 Oncogene; Involved in PI3K/AKT pathway which regulates Non-secreting adenomas
kinases several cellular functions, including cell survival, growth,
proliferation, and metabolism
CDKN2A Cyclin dependent Kinase 9p21 Tumor supperessor; Cell cycle regulation (G1 to S phase Non-secreting adenomas and
Inhibitor 2A transition) somatotroph adenomas
(Continued)

TABLE 1 | Continued
ENC1 Ectodermal-neural cortex 1 5q13.3 Unknown Null cell adenomas

MEG3 Maternally expressed 3 14q32.2 Tumor supperessor; suppress tumor genesis by both p53- Non-secreting adenomas
dependent and p53-independent pathways.
ING2 Inhibitor of growth family 4q35.1 Unknown Non-secreting adenomas
member 2
FAM90A1 family with sequence 12p13.31 Unknown Non-secreting adenomas
similarity 90 member a1
upregulate ZAC1 mRNA expression (51, 52). Disordered cAMP Less Common Genetic Variations Potentially
regulation is important for the resistance of AIP mutations to Associated With Pituitary Adenomas
SSA treatment (42, 49). Pituitary tumor-transforming gene 1 (PTTG1) is overexpressed
in various pituitary tumors, and its expression is higher in more
Guanine Nucleotide-Binding Protein G(s) aggressive tumors (62–64). Somatotroph adenomas with
Subunit Alpha recurrent aneuploidy have relatively high expression of PTTG1;
GNAS encodes the stimulatory a subunit of the G protein complex, as a regulator of sister chromatid segregation, this may
which plays an important role in transmembrane signal subsequently drive chromosomal instability (64–66).
transduction (53). Its mutation rate is the highest of somatic
mutations in somatotroph adenomas (up to 40%). GNAS-mutated Signal Transducer and Activator
tumors are often smaller and less invasive, respond better to SSAs, of Transcription 3
and are usually densely granulated somatotroph adenomas (52, 54, STAT3 is a member of the STAT family, and participates in
55). In addition, GNAS-mutated tumors have relatively high cellular responses to cytokines and growth factors (67). Its
expression of dopamine receptor (DRD) 2, which suggests a good expression is enhanced in somatotroph adenomas, leading to
response to dopamine agonists (38). Somatic mutations in GNAS GH hypersecretion, which in turn promotes STAT3 expression
can result in sporadic somatotroph adenomas, while mosaic (68). In primary human somatotroph adenoma-derived cell
mutations for codon 201 likely result in McCune–Albright cultures, the specific inhibitor S3I-201 can inhibit STAT3
syndrome. This syndrome is characterized by polyostotic fibrous expression, thus decreasing GH transcription and reducing GH
dysplasia, skin hyperpigmentation, and autonomous endocrine secretion (68).
hyperfunction (56).
GNAS mutations can also lead to disruption of the cAMP CDH23
signaling pathway. Especially, mutations in codon 201 or 227 CDH23 is involved in Wnt pathway regulation. The CDH23
result in the inhibition of G proteins and the activation of c.4136G>T (p.Arg1379Leu) mutation leads to an amino acid
adenylyl cyclase, promote cAMP synthesis in cells, and drive substitution in the calcium-binding motif of the extracellular
tumorigenesis (57). Recently, a GNAS mutation (p.Arg201Cys) cadherin domain, which is predicted to disrupt cell–cell
has been detected as a recurrent somatic event, and this mutation adhesion. The incidence rate of CDH23 mutations is 33% in
is shared with chromosome losses (58, 59). FIPA patients and 12% in sporadic PA patients. Of the CDH23-
mutated PAs, somatotroph adenomas account for the highest
Copy Number Variations at the Chromosomal Level proportion (25.9%) (69). PAs with functional CDH23 variants
Recent studies have indicated that increased cAMP in are smaller and less aggressive compared with non-mutated PAs
tumorigenesis can probably induce DNA damage, leading to (69, 70). In addition, variants in this gene are associated with
somatic CNVs and genome instability (60). Of these, arm-level Usher syndrome (70). However, CDH23 variations have been
CNVs are the most common abnormalities in somatotroph reported in only one study, and functional validation studies
adenomas. Specifically, whole chromosome losses are needed.
(chromosomes 1, 6, 13, 14, 15, 16, 18, and 22) and gains
(chromosomes 3, 5, 7, 10, 19, 20, and X) have been observed Immunoglobulin Superfamily Member 1
(58, 59, 61). Interestingly, GNAS mutation-positive adenomas IGSF1 is a membrane glycoprotein. IGSF1 mutations can weaken
have relatively low CNV levels, whereas GNAS mutation- its transport to the cell surface in allogenic cells, resulting in a
negative adenomas have a high degree of genomic disruption novel X-related syndrome. This syndrome is characterized by
(58, 59, 61). These CNVs likely affect the Ca2+ and ATP central hypothyroidism, macro-orchidism, and prolactin
pathways, which are involved in PA tumorigenesis (58, 59, 61). deficiency (71–73). It can also be associated with acromegaloid
Thus, the CNVs in GNAS mutation-negative somatotroph facial features, increased head circumference, and increased total
adenomas provide an alternative tumorigenic pathway, which GH secretion and IGF-1 levels. However, considering that
is linked to genomic instability (58, 59, 61). patients present with hyperplasia rather than adenomas, these

symptoms may be secondary to the failure of regulatory and miRNA Regulation

feedback mechanisms. miRNA binding to the 3’ and 5’ untranslated regions and coding
sequences of target RNA is a form of post-transcriptional
Solute Carrier Family 20 Member 1 modification that results in differential gene expression.
SLC20A1 levels are positively associated with tumor size, invasive miRNAs play an important role in various pathways in tumors.
behavior, and recurrence in somatotroph adenomas. In addition,
increased SLC20A1 expression may be associated with activation High-Mobility Group AT-Hook 1/2 Regulation
of the Wnt–b−catenin signaling pathway (74). Palumbo et al (85). reported that miRNAs that target HMGA,
including miR-15, miR-16, miR-26a, let-7a, miR-196a2, and
PR Domain Zinc Finger Protein 2 other miRNAs, are downregulated in PAs. These HMGA-
PRDM2, a tumor suppressor, plays an important role in cancer targeting miRNAs have also been demonstrated to inhibit the
and obesity, including PAs. The absence of PRDM2 is likely to be proliferation of a somatotroph adenoma cell line (GH3) and
involved in the tumorigenesis of somatotroph adenomas by promote pituitary tumorigenesis. Furthermore, D’Angelo et al.
regulating c-Myc (75). However, this discovery remains to be reported that downregulated miRNAs, including miR-326, miR-
validated by more investigation groups. 570, and miR-432, target HMGA1 and HMGA2; while miR-34b
and miR-548c-3p target HMGA2; and miR-603 and miR-326
Somatostatin Receptors and Dopamine Receptors target E2F transcription factor 1 (E2F1). In addition, some
SSTR (SSTR1–5) and DRD (DRD1–5) subtypes play critical roles miRNAs are downregulated in somatotroph adenomas,
in the regulation of hormone secretion (76). Decreased including miR-34b, miR-326, miR-432, miR-548c-3p, miR-570,
expression of some of these receptors (DRD4, DRD5, SSTR1, and miR-603 (86). The long non-coding RNA (lncRNA)
and SSTR2) may be associated with a poor response to SSAs (77). ribosomal protein SA pseudogene 52 (RPSAP52) is
In particular, SSTR2 expression might be a good predictor of a overexpressed in PAs. It promotes cell proliferation in a
patient’s response to SSAs (78). competing endogenous RNA (ceRNA)-dependent manner by
competitively binding to miR-15a, miR-15b, and miR-16, and by
DNA Methylation upregulating the expression of HMGA1 and HMGA2 (87, 88).
DNA methylation is the most frequently studied epigenetic
phenomenon, in which alterations of CpG dinucleotides block Phosphatase and Tensin Homolog –Protein Kinase B
the transcriptional mechanism and silence gene expression (79). Pathway
Approximately 80% of CpG dinucleotides are methylated in the Downregulated and upregulated miRNAs sometimes work
human genome throughout the lifespan, and nearly 70% of CpG together. For example, the downregulation of miR-26b expression
islands are methylated at any time, suggesting a widespread together with the upregulation of miR-128 suppresses colony
regulatory scope of DNA methylation (80). Here, we summarize formation ability and invasiveness, and regulates the activity of
the methylated genes in somatotroph adenomas (Table 1). the PTEN–AKT pathway in somatotroph adenomas (85).
Growth arrest and DNA damage-inducible gene (GADD45g)
is a negative regulator of cell growth that is involved in DNA PTTG1 Regulation
damage repair. In one study, most PAs (22/33, 67%) did not have Multiple miRNAs are associated with the increased expression of
GADD45g expression, and 57.6% (19/33) of PAs were detected PTTG1. First, miR-338-3p is upregulated in invasive somatotroph
with GADD45g methylation; there was significantly associated adenomas, and probably mediates the increased expression of
between GADD45g methylated tumors and tumors in which PTTG1 (89). Second, miR-423-5p, which targets PTTG1, shows
GADD45g transcript was not expressed (18 of 22; 82%; P = decreased expression in somatotroph adenomas, and inhibits the
0.002) (81). The silencing of GADD45g is likely to confer a expression of PTTG1 at both the mRNA and protein levels (90).
selective growth advantage during PA tumorigenesis (82). Third, overexpression of miR-524-5p downregulates the
The importance of the promoter methylation status of LGALS3 expression of PTTG1-binding factor, which interacts with
(the gene encoding galectin-3) for the regulation of galectin-3 PTTG1 to mediate downstream effects, and significantly
expression in PA was confirmed by Ruebel et al. Ikaros, a factor attenuates proliferation, migration, and invasion in vitro (91).
with transcriptional functions and chromatin-remodeling properties
that determine the fate of hypothalamic neuroendocrine and pituitary
cell populations during development, may also contribute to the
expression of galectin-3 (83). CORTICOTROPIN-SECRETING
The human Ras-association domain family 1A (RASSF1A) ADENOMAS
gene has been reported as frequently (38%, 20/52)
hypermethylated in its promoter region in all types of PAs. Corticotropin-secreting adenomas account for 15% of PAs, with
RASSF1A promoter methylation is relatively low in gonadotroph an incidence of 1.6 cases per 1 million individuals. These
cell adenomas, higher in the most aggressive adenomas, and adenomas are typically small, and the excessive secretion of
potentially correlated with Ki-67 expression. Reduced expression corticotropin leads to adrenal hypercortisolemia (92). Although
of RASSF1A has been identified in 18 of 20 (90%) adenomas with 75% of patients achieve remission after surgical treatment,
hypermethylation of RASSF1A (84). recurrence occurs in approximately 10% of these patients (93).

Current pituitary-targeted drugs, including cabergoline and proteins are direct or indirect clients of USP8 and could
pasireotide, can improve the clinical features of excessive therefore be potential targets for treatment (99).
hormone secretion, but 60–75% of patients are insensitive to USP8 mutations have also been identified in silent
these drugs, which cannot control the symptoms long after drug corticotroph adenomas (100). Transcriptomic profiles show
treatment (94). Therefore, an understanding of the molecular significant differences between functioning and silent
characteristics of these tumors is necessary to identify additional corticotroph adenomas. However, USP8 mutations have
drug targets. Here, we summarize the abnormal alterations in pleiotropic effects in both functioning and silent corticotroph
corticotropin-secreting adenomas that may serve as potential adenomas, and affect the expression levels of many genes that are
therapeutic targets (Figure 2, Table 1). involved in a range of different pathways (100).
Germline USP8 mutations, which are commonly found as
Genetic Variations somatic mutations in corticotropin-secreting adenomas, have
Ubiquitin-Specific Peptidase 8 also recently been described in a child with dysmorphic features,
USP8 encodes a deubiquitinase enzyme that protects epidermal developmental delay, and a corticotroph adenoma (101). In
growth factor receptor (EGFR) from degradation. Up to 62.4% of addition, an overall prevalence of USP8 mutations of 32% has
corticotropin-secreting adenomas were found to have USP8 been reported in corticotropin-secreting adenomas. USP8-
mutations that block 14-3-3 protein binding, leading to mutated tumors are more common in females, and are
increased activity of USP8 (95–97). Gain-of-function associated with earlier onset (96, 102), a smaller size (95), and
mutations in USP8 increase the deubiquitination of EGFR, increased ACTH production (95, 102). Patients with USP8-
which inhibits its degradation, leading to the activation of mutated tumors are more likely to go into initial remission
EGFR signaling. This mechanism likely leads to the synthesis after surgery, but may also be more likely to show recurrence
and secretion of adrenocorticotropic hormone (ACTH) and later in the clinical course (102–104). In contrast, USP8-
promotes tumorigenesis (95–98). In USP8-mutated mutation-negative tumors are more likely to show sphenoid
corticotropin-secreting adenoma samples, the cell cycle invasion with an increased epithelial–mesenchymal transition
inhibitor p27, heat shock protein 90 (HSP90), and signature (38). Lapatinib, an EGFR inhibitor, decreases
phosphorylated cAMP-response element binding protein proliferation in vitro and reduces tumor weight in vivo (105).
(pCREB) were significantly reduced, suggesting that these In addition, SSTR5 expression is higher in USP8-mutated tumors
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.

(38, 106), potentially allowing mutation status to be used as a in patients with other types of PAs, and to elucidate the pituitary-
predictor of response to pasireotide (a second-generation SSA specific functions of this gene (111).
with a greater affinity for SSTR5) (107).
Secreted Frizzled−Related Protein 2 (SFRP2)
The RNA and protein expression of SFRP2 is decreased in
USP48 and BRAF
corticotroph adenomas compared with normal pituitary glands
With the recognition of the importance of USP8 mutations, another
(112). In addition, the overexpression of SFRP2 in AtT20 cells
two mutated genes in the mitogen-activated protein kinase (MAPK)
reduces b−catenin levels in the cytoplasm and nucleus, and also
pathway, USP48 and BRAF, have also been detected in
decreases Wnt signaling activity. SFRP2 may therefore act as a
corticotropin-secreting adenomas (108). Missense mutations in
tumor suppressor in Cushing’s disease by regulating Wnt
USP48 include M415I/V substitutions, while V600E is an
signaling pathway activity. Clinically, there is an association
activation mutation of BRAF. Among tumors without USP8
between lower SFRP2 expression and aggressive adenoma
mutations, 23% of corticotropin-secreting adenomas have USP48
characteristics, including a larger size and invasiveness (112).
mutations and 16% have BRAF mutations (108). Both mutations
enhance the promoter activity and transcription of the ACTH
DNA Methylation
precursor, the proopiomelanocortin (POMC) gene, and are
Although some corticotropin-secreting adenomas have been
potential therapeutic targets for the excess secretion of ACTH in
found to have genetic mutations, the pathogenesis of non-
corticotropin-secreting adenomas. Furthermore, USP48 variants are
mutated adenomas remains unknown. DNA methylation, a
associated with smaller tumors and a better response to
complementary mechanism for gene mutations, also plays an
corticotropin-releasing hormone (CRH) stimulation (109).
important role in PAs.
Therefore, variations in EGFR regulation, the MAPK pathway,
and POMC-related genes play a certain role in corticotropin-
POMC
secreting adenomas.
Hypomethylation of the promoter of POMC, which encodes the
precursor of ACTH, leads to the occurrence of corticotropin-
Less Common Genetic Variations Potentially secreting adenomas. A comparison of the methylation profiles of
Associated With Pituitary Adenomas ACTH-PAs and NF-PAs showed that the overexpression of
Heat Shock Protein 90 (HSP90) POMC likely accounts for promoter hypomethylation (3). As a
Corticotroph adenomas overexpress HSP90 compared with the pituitary hormone, ACTH leads to increased serum cortisol
normal pituitary gland. N- and C-terminal HSP90 inhibitors act levels in patients with Cushing’s disease, which is associated
at different stages of the HSP90 catalytic cycle to regulate with the occurrence of corticotropin-secreting adenomas.
corticotropic cell proliferation and glucocorticoid (Gc) receptor
(GR) transcriptional activity. The C-terminal HSP90 inhibitor Fibroblast Growth Factor 2
silibinin has been reported to have anti-tumorigenic effects, FGF2 is a potent growth factor that regulates stem cell
partially decrease hormonal secretions, and alleviate the maintenance and neurogenesis during embryonic development
symptoms of Cushing’s disease in a mouse model (110). and in response to challenges such as stress or injury in the adult
Brg1 and Histone Deacetylase 2 brain (113–117). FGFR2 encodes a growth factor receptor, and
The negative feedback regulation of POMC by GRs is a critical was found to be methylated by a 5’ promoter in mouse AtT20
feature of the hypothalamo–pituitary–adrenal axis. Loss of Brg1 or cells, leading to significantly downregulated expression (80).
HDAC2 should therefore produce Gc resistance, and we have
previously shown that approximately 50% of Gc-resistant human Pituitary Tumor Apoptosis Gene
and dog corticotropin-secreting adenomas, which are the hallmark In a model pituitary tumor cell line (AtT20), enforced expression
of Cushing’s disease, have deficient nuclear expression of either of of PTAG is associated with significantly increased sensitivity to
these proteins. In addition to providing a molecular basis for Gc the apoptotic effects induced by bromocriptine challenge (118).
resistance, Brg1 and HDAC2 deficiencies may also contribute to
the tumorigenic process (111). Thrombospondin-1
The secreted angioinhibitory factor TSP-1 is an adhesive
CDK5 and ABL1 Enzyme Substrate 1 glycoprotein that mediates cell-to-cell and cell-to-matrix
CABLES1 is a cell cycle regulator that participates in the adrenal– interactions, and is associated with platelet aggregation,
pituitary negative feedback loop. Four heterozygous germline angiogenesis, and tumorigenesis. Overexpression of TSP-1 in a
missense variants have been identified in CABLES1 in four murine AtT20 pituitary corticotroph tumor cell line leads to
sporadic patients from a cohort of 182 patients with corticotropin- increased ACTH secretion (119).
secreting adenomas, with functional evidence. The four variants
affected residues within or close to the predicted cyclin-dependent ESR1 and Caspase 8
kinase-3 (CDK3)-binding region of the CABLES1 protein and The methylation levels of ESR1 and CASP8 in corticotropin-secreting
impaired its ability to block cell growth in a mouse adenomas are also increased compared with those of silent
corticotropinoma cell line (AtT20/D16v-F2). However, further corticotroph adenomas. CASP8 plays an important role in
studies are needed to assess the prevalence of CABLES1 mutations apoptosis. Furthermore, CASP8 has been suggested to affect the

functional behavior of corticotroph adenomas, but the specific (123). These results indicate that C5orf66-AS1 suppresses the
mechanisms remain unknown. The methylation of POMC, FGFR2, development and invasion of pituitary null cell adenomas (123).
RASSF1A, LGALS3, and apoptosis-related factors plays a potential
role in the development of corticotropin-secreting adenomas. Interleukin 6 Receptor (IL-6R)/Janus Kinase 2
(JAK2)/STAT3/Matrix Metallopeptidase 9
MiRNA Regulation Integrative proteomics and transcriptomics have revealed the
The tumor suppressors miR-15a, miR-16, and miR-132 are activation of IL6R, JAK2, and STAT3, and the overexpression of
downregulated in corticotroph adenomas. These miRNAs IL-6R, JAK2, STAT3, p-STAT3, and MMP9, in invasive pituitary
inhibit the proliferation, invasion, and migration of pituitary null cell adenomas (125). Therefore, activation of the IL-6R–
tumor cells by targeting sex-determining region Y-box 5 (SOX5) JAK2–STAT3–MMP9 signaling pathway is correlated with the
(120). In addition, the following miRNAs are also reportedly invasiveness of pituitary null cell adenomas.
downregulated in corticotroph adenomas: miR-145 (2.0 fold),
miR-21 (2.4 fold), miR-141 (2.6 fold), let-7a (3.3 fold), miR-150 Genetic Variations in Silent Somatotroph Adenomas
(3.8 fold), and miR-143 (6.4 fold), suggesting that they may play Somatostatin Receptor 2 and Dopamine Receptor2
a role in the tumorigenesis of corticotropin-secreting adenomas. There is a negative correlation between SSTR2 and tumor size in
miR-26a is overexpressed in corticotroph adenomas, and one of silent somatotroph adenomas. Additionally, levels of DRD2
its direct targets is protein kinase Cd (PRKCD) (85). PRKCD expression are reportedly similar between silent and
silencing is associated with increased EGFR expression, functioning somatotroph adenomas, suggesting a possible basis
indicating PRKCD as a possible molecular target for the for the treatment of these tumors with SSAs and dopamine (126).
treatment of corticotroph adenomas (121, 122).
Genetic Variations in Non-Secreting Tumors Without
Classification
NON-SECRETING ADENOMAS Phosphatidylinositol 3-Kinases
PI3K is an important regulator of cell growth, transformation,
Non-secreting adenomas account for 20–35% of PAs originating adhesion, apoptosis, survival, and movement. The catalytic
from different hormone-secreting cells. Many of these are subunit encoding the PIK3CA gene is located on chromosome
gonadotroph adenomas, and some show somatotroph, 3q26.3 and is often found to be deficient in cancer (127). Somatic
corticotroph, thyrotroph, or lactotroph differentiation. In older mutations have been detected in 8 out of 91 (9%) of invasive
studies, the diagnosis of non-functional adenomas was mainly pituitary tumors versus 0 out of 262 (0%) non-invasive tumors
based on the normal results of hormone secretion rather than the (128). In addition to mutations of PI3K, mutations of MEN1, AIP
results of immunohistochemical staining. However, with recently (129), and CDH23 (69) have also been detected in non-secreting
updated pituitary tumor classifications, the diagnosis of non- adenomas. In this section, we summarize the gene mutations in
functional adenomas is made according to detailed pituitary cell cell cycle regulators, phosphokinase, the cAMP signaling
types. Because excessive hormone levels are not found in the pathway, and cadherin that are associated with the occurrence
blood with non-secreting adenomas, they may not be detected of non-secreting adenomas.
for years in patients, and are often diagnosed incidentally (92).
Although mostly benign, some invasive pituitary tumors require DNA Methylation
adjuvant radiation after surgery, often resulting in pituitary The p16 protein, encoded by the tumor suppressor gene
failure and a risk of recurrence. In an effort to aid in the CDKN2A, is located on chromosome 9p21. CDKN2A has been
development of additional treatment methods, we herein found to exhibit deletions, point mutations, or methylation
summarize the molecular signatures of non-secreting inactivation in a variety of tumors. Methylation of the CpG
adenomas (Table 1). island of CDKN2A was detected in 32/46 (70%) non-secreting
adenomas, in contrast to 2/21 (9.5%) somatotroph adenomas
Genetic Variations in Null Cell Adenomas and 0/15 histologically normal postmortem pituitaries (130).
C5orf66-AS1 Methylation of CDKN2A corresponds to a loss of p16
C5orf66-AS1 encodes a lncRNA that is differentially expressed expression on immunohistochemical analysis (130). When p16
between pituitary null cell adenoma tissues and normal pituitary is silenced, retinoblastoma protein (encoded by RB1) becomes
tissues, as well as between invasive and non-invasive tumors phosphorylated, which enables cell cycle progression via the
(123). Co-expression analysis in RNA sequencing data revealed activation of E2F transcription factors (80). These observations
that PAQR7 [a membrane progesterone receptor that may indicate that the CDKN2A-related pathway is a potential target
mediate a reduction in gonadotropin-releasing hormone in the for non-secreting adenoma cell proliferation.
progesterone negative feedback action in a progesterone receptor
(A/B)-independent way (124)] was the gene that was most Maternally Expressed 3
correlated with C5orf66-AS1, and several predicted trans-acting MEG3 is a maternally expressed imprinted lncRNA that is
target genes, including SCGB3A1 (encoding secretoglobin family transcribed from multiple transcriptional variants with
3A member 1), were also highly correlated with C5orf66-AS1 different splicing patterns, all of which are lncRNAs. Several

studies have shown that MEG3-encoded lncRNA is a tumor HMGA1 and HMGA2
suppressor that interacts with p53 and regulates expression of the HMGA proteins comprise a family of transcriptional regulating
p53 gene (TP53) (79, 131). In NF-PAs, MEG3 was found to be factors that are highly expressed during embryogenesis and play
hypermethylated in both the 5’ region of the first exon and an important role in tumorigenesis in various tissues, including
approximately 1.6–2.1 kb upstream of the first exon, leading to the pituitary gland. HMGA2 has been shown to be rearranged
the silencing of gene expression (79). Hypermethylation in the and amplified in lactotroph adenomas, and transgenic mice with
regulated area of MEG3 is an important mechanism that likely Hmga2 overexpression develop PAs with prolactin and GH
leads to the loss of MEG3 expression in clinical NF-PAs. secretion (137). The primary mechanism by which HMGA2
mutations lead to PAs involves an increase in E2F1 activity
Ectodermal-Neural Cortex 1 (138). It has also been reported that MIA is one of the most
Methylated ENC1 has been found in tumor samples, and commonly downregulated genes in lactotroph adenomas, and this
decreased levels were detected compared with normal pituitary may serve as a downstream mechanism of HMGA2 (137, 139). The
glands (132). Notably, ENC1 expression levels are reportedly HMGA2 protein can bind to the DNA elements of pituitary-
lower in invasive null cell adenomas than in non-invasive specific positive transcription factor 1 (PIT-1) and cause a PIT-1
adenomas (133, 134). reaction, thus positively regulating the production of the PIT-1
promoter. It is therefore speculated that HMGA2 leads to the
Inhibitor of Growth Family Member 2 proliferation of PIT-1-expressing cells or the abnormal
ING2 is a member of the growth inhibitor family, and participates in proliferation of GH- and prolactin-secreting embryonic cells
regulating the activity of histone acetyltransferase and histone (137, 140). In addition, the downregulation of miRNAs may be
deacetylase complexes, and plays a role in DNA repair and related to the accumulation of HMGA2, which might lead to the
apoptosis. Methylation sequencing of NF-PAs revealed the proliferation of pituitary cells. In one study, the expression of miR-
presence of ING2 DNA methylation in NF-PAs, and the let-7 was reported to be decreased in 23 of 55 (42%) lactotroph
methylation and expression levels were correlated with tumor adenomas, and was negatively correlated with the expression of
recurrence. Furthermore, clinical data have indicated that ING2 is HMGA2 (141). The overexpression of HMGA2 protein is also
an independent prognostic marker of NF-PAs (135). positively correlated with pituitary tumor phenotype, and
overexpression of Hmga2 in transgenic mice results in the
Family with Sequence Similarity 90 Member A1 development of PA (142). Therefore, HMGA2 is a specific
FAM90A1 is a primate-specific gene that is associated with ING2. oncogene for pituitary transformation. However, according to the
FAM90A1 is also hypermethylated in NF-PAs, and the current evidence that has been collected on genes in the HMGA
methylation level is significantly correlated with patient family, only HMGA2 has a direct causal role in human pituitary
prognosis (135). FAM90A1 methylation likely plays a role in tumorigenesis because it is amplified or rearranged in human
NF-PA tumorigenesis and is a potential marker of PA. lactotroph adenomas. It has been reported that HMGA1 and
HMGA2 nuclear expression levels are significantly higher in
Common Methylations with Somatotroph Adenomas invasive adenomas than in non-invasive adenomas (143, 144).
Similar to somatotroph adenomas, NF-PAs also exhibit
hypermethylation in the CpG island of the GADD45g gene. In Prolactin Receptor
addition, the methylation of CDKN2A, MEG3, and RASSF1A has The deletion of the PRLR-encoding gene leads to aggressive
also been detected in NF-PAs. Most methylated genes are pituitary tumors in mice, while homozygous deletion mutants of
involved in the cell cycle and DNA damage repair. However, PRLR in patients with hyperprolactinemia and agalactia do not
novel abnormally methylated genes, such as ING2 and lead to pituitary tumors (145). In contrast, a gain-of-function
FAM90A1, have also been detected, and their specific mutation was found in 9 of 46 patients with lactotroph
regulatory mechanisms remain unknown. adenomas, representing a potential novel mechanism for
lactotroph adenoma tumorigenesis. In addition, three other
rare variants and two low-frequency variants found in this
LACTOTROPH ADENOMAS cohort may represent benign changes (146). However, further
investigations are needed to confirm the underlying mechanisms.
Lactotroph adenomas are the most common secretory tumors,
accounting for 60% of all PAs. Microprolactinomas are usually
stable and slow growing, and continued growth after diagnosis THYROTROPH ADENOMAS
occurs in less than 15% of cases (2). Lactotroph adenomas are
ideally managed with dopamine agonists (136). Dopamine agonists Thyrotroph adenomas are the least common type of PAs,
can reduce prolactin levels and shrink tumors; however, they have accounting for approximately 1% of all adenomas. Thyrotroph
side effects, and 15% of patients are not sensitive to these drugs (2). adenomas lead to elevated or inappropriately suppressed
Additional targets are therefore needed to improve lactotroph thyrotropin levels, with normal or elevated thyroid hormone
adenoma treatment. Here, we summarize the molecular variations levels. Sapkota et al. confirmed six DNA variants as candidate
that occur in lactotroph adenomas. driver mutations; two of these mutations were identified in genes

with an established role in malignant tumorigenesis (SMOX and Implications for therapy. In a subset of pituitary tumors that are
SYTL3), while four had unknown roles (ZSCAN23, ASTN2, refractory to routine therapy, both MGMT promoter
R3HDM2, and CWH43) (147). Similarly, a single nucleotide hypermethylation in aggressive PAs and pituitary carcinomas and
polymorphism array analysis revealed frequent chromosomal low protein expression have been implicated. Hypermethylation of
regions of copy number gains, including recurrent gains at the MGMT indicates a better response to treatment with temozolomide
loci harboring four of these six genes. In addition, Ando et al. (TMZ) in some aggressive PAs (155). In one study, combination
reported a somatic mutation in the ligand-binding domain of treatment with TMZ and pyrimethamine (PYR) produced
thyroid hormone receptor beta (TRbeta) that causes a His to Tyr synergistic antitumor activity both in vivo and in vitro. Moreover,
substitution at codon 435 of TRbeta1, corresponding to codon TMZ/PYR treatment induced cell cycle arrest, increased DNA
450 of TRbeta2 (148). Unlike other PAs, thyrotroph adenomas damage, and upregulated the expression of cathepsin B, BAX,
are rarely associated with genetic syndromes or common cleaved PARP, and phosphorylated histone H2AX; it also elevated
somatic mutations. caspase 3/7, 8, and 9 activities. Therefore, PYR may enhance the
efficacy of TMZ by triggering both cathepsin B- and caspase-
dependent apoptotic pathways. A combination of PYR and TMZ
may thus provide a novel regimen for invasive PAs that are
ALL TYPES refractory to standard therapy and TMZ alone (156).
Gain or loss of chromosome. A non‐random gain in pituitary
tumors has been reported in chromosomes 5, 8, 12, and X (149,
150). Gains of chromosomes 8 and 12 were found in prolactinomas
CONCLUSION
and non-secreting adenomas, whereas a combined loss of
chromosomes 5 and 8 was observed in corticotroph and We reviewed older and more recent discoveries of molecular
somatotroph adenomas. In addition, recurrent structural variations in somatotroph adenomas, corticotroph adenomas,
rearrangements affecting chromosomes 1, 3, and 12 have also lactotroph adenomas, non-secreting adenomas, and thyrotroph
been identified in prolactinomas, which appear to be the only PA adenomas. Summarizing the genetic and epigenetic markers of
subtype with a defined trend of tumor‐specific chromosomal different types of PAs and elucidating their comprehensive
changes (149). In another whole-exome sequencing investigation, molecular mechanisms will be helpful to identify the
75% of the highly disrupted group were functional adenomas or physiological pathways of PAs. These findings will provide a
atypical null cell adenomas, whereas 87% of the less-disrupted better understanding of the occurrence of PAs and lead to the
group were non-functional adenomas (151). The disrupted development of novel therapeutic treatments.
samples were characterized by expression changes associated with
poor outcomes in other cancers. Furthermore, arm-level losses of
chromosomes 1, 2, 11, and 18 were significantly recurrent (151).
These data indicate that sporadic PAs have distinct copy-number AUTHOR CONTRIBUTIONS
profiles that are associated with hormonal and histological subtypes
and influence gene expression. CM wrote the manuscript of this paper, and YC helped in
Transcription factors. Cell lineages of the pituitary are dependent modifying the manuscript. BX and WR directed the
on the expression of the pituitary transcription factors PIT1, TPIT, manuscript. All authors contributed to the article and
and SF1 that, in concert with ERa and GATA2/3, regulate cellular approved the submitted version.
differentiation and hormone secretion (152). Recently, these
transcription factors (PIT1 for GH, prolactin, and TSH lineages;
SF1 for gonadotroph lineages; and TPIT for ACTH lineages) have FUNDING
been added to the classification (152, 153).
DNA methylation. Frequently methylated genes (i.e., CDKN2A, This work was supported by the National Key R&D Program of
GADD45y, FGFR2, CASP8, and PTAG) demonstrate methylation in China (2018YFA0108602, 2018YFA0108600 to XB), China
over 50% of PAs; moderately methylated genes (i.e., TSP-1, RASSF1A, Postdoctoral Science Foundation (BX20190045 to MC), Beijing
RB1, p73, MGMT, and CDH1) demonstrate methylation in 20–50% Municipal Natural Science Foundation (7182134 to XB), CAMS
of PAs; and infrequently methylated genes (i.e., p14, DAPK1, TIMP3, Initiative for Innovative Medicine (CAMSI2M) (2016-I2M-1-017 to
p21, and p27) are methylated in less than 20% of PAs (79, 154). These XB), CAMS Young Talents Award Project (2018RC320003 to XB),
variable rates of methylation may reflect a variety of factors. and Beijing Nova Program (Z181100006218003 to XB).
2. Melmed S. Pituitary-Tumor Endocrinopathies. N Engl J Med (2020) 382

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published: 26 January 2021

Genetic and Epigenetic Causes

Pituitary adenomas (PAs) can be classiﬁed as non-secreting adenomas, somatotroph

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Von Hippel–Lindau Syndrome Genetic Variations

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ENC1 Ectodermal-neural cortex 1 5q13.3 Unknown Null cell adenomas

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symptoms may be secondary to the failure of regulatory and miRNA Regulation

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2. Melmed S. Pituitary-Tumor Endocrinopathies. N Engl J Med (2020) 382

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