Genetic and Epigenetic Pathogenesis of Acromegaly

Abstract

Acromegaly is caused by excessive secretion of GH and IGF-I mostly from somatotroph tumors. Various genetic and epigenetic factors are involved in the pathogenesis of somatotroph tumors. While somatic mutations of GNAS are the most prevalent cause of somatotroph tumors, germline mutations in various genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) are also known as the cause of somatotroph tumors. Moreover, recent findings based on multiple perspectives of the pangenomic approach including genome, transcriptome, and methylome analyses, histological characterization, genomic instability, and possible involvement of miRNAs have gradually unveiled the whole landscape of the underlying mechanisms of somatotroph tumors. In this review, we will focus on the recent advances in genetic and epigenetic pathogenesis of somatotroph tumors.

Transcriptomic Profiles of Normal Pituitary Cells and Pituitary Neuroendocrine Tumor Cells

“…These mutations have been gain-of-function GNAS mutations resulting in constitutive activation of adenylyl cyclase and autonomous secretion of growth hormone [65][66][67][68]. GNAS mutations are more commonly found in smaller-sized somatotroph PitNETs and are associated with the densely granulated variant on histology [69]. Some studies suggest that GNAS mutation is associated with a better response to somatostatin receptor analogs but these findings are not consistent in the literature and require further investigation [46,[70][71][72].…”

Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives

“…A large majority of acromegaly cases are caused by a pituitary adenoma while a small percentage can be due to inherited genetic mutations that predispose to pituitary adenomas. Mutations in genes such as multiple endocrine neoplasia type 1 ( MEN1 ), aryl hydrocarbon receptor-interacting protein ( AIP ) and G protein-coupled receptor 101 (GPR101) have been implicated ( Yamamoto and Takahashi, 2022 ). The clinical features of acromegaly include gradual enlargement of the hands and feet.…”

Tall stature and gigantism in transition age: clinical and genetic aspects—a literature review and recommendations

“…Carney complex syndrome (CCS) is a rare genetic syndrome including multiple endocrine and non-endocrine neoplasms, whose diagnosis is based on the presence of two or more of the following manifestations: skin pigmentation, cardiac myxomas, primary pigmented nodular adrenocortical lesions, large cell calcifying Sertoli cell tumours, ductal adenomas, pustular melanomas, blue naevi, osteochondral myxomas, thyroid tumours, and acromegaly [ 86 ]. In 30% of cases, it is caused by de novo mutations in the suppressor gene for PRKAR1A ( CNC1 ) at 17q24.2, encoding for the regulatory subunit type 1α of the protein kinase A [ 87 ].…”

“…In 30% of cases, it is caused by de novo mutations in the suppressor gene for PRKAR1A ( CNC1 ) at 17q24.2, encoding for the regulatory subunit type 1α of the protein kinase A [ 87 ]. CCS is generally diagnosed over 20 years of age; in this context, acromegaly is observed in 10–18% of cases, with a female predominance [ 86 ]. In a French multicentre prospective study including 70 CCS patients (50 females, mean age 35.4 ± 16.7 years, 81% carrying a PRKAR1A gene mutation), annual systematic screening highlighted that acromegaly had a prevalence of 18%, although clinical signs of GH excess were generally mild or absent.…”