Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

Abstract

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

SFRP2 is a Novel Diagnostic Biomarker and Suppresses the Proliferation of Pituitary Adenoma

“…It is unknown how common malignant prolactin-secreting pituitary tumors are. It is common for them to develop resistance to standard treatments such as TMZ and to experience rapid recurrence after surgery [28,29].…”

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

“…Pituitary adenomas are usually benign intracranial tumors that are classified as functional (secretory) or non-functional tumors, and categorized based on their mass (micro- or macroadenomas) and the specific pituitary hormone that they release [ 18 , 227 ]. A few years ago, the International Pituitary Pathology Club suggested renaming pituitary adenomas as pituitary neuroendocrine tumors (PitNET) [ 228 ].…”

“…In these cells, the GHRH receptor (GHRH-R) is coupled to stimulatory heterotrimeric G protein (Gs) and adenylyl cyclase activation. As for human GH-secreting pituitary adenomas, about 40% of patients with sporadic acromegaly harbor guanine nucleotide-binding protein alpha stimulating (GNAS) gene mutations, leading to constitutively elevated cAMP levels [ 227 , 230 , 231 ].…”

Emerging Roles of miRNA, lncRNA, circRNA, and Their Cross-Talk in Pituitary Adenoma

“…Consequently, they are divided into functional PAs (FPAs) and non-functional PAs (NFPAs). FPAs include growth hormone (GH)-, prolactin (PRL)-, adrenocorticotropic hormone (ACTH)-, thyroid-stimulating hormone (TSH)-, and follicle-stimulating hormone/luteinizing hormone (FSH/LH)-secreting adenomas [ 4 , 5 ]. Some proteins are involved in the pathogenesis of PA subtypes.…”