Expression of cell-cycle regulating proteins and pro-opiomelanocortin transcription factors in Cushings disease - a somatic mutation-based analysis

Abstract

Cushing's disease (CD) is defined by the presence of autonomous ACTH secretion by a pituitary adenoma, wich leads to excessive cortisol production by the adrenal glands. One of the illnesses' hallmarks is resistance to cortisol negative feedback over ACTH secretion, wich perpetuates hypercortisolism.Recently, important developments have been made regarding the elucidation of the molecular mechanisms involved in tumorigenesis in CD. In 2015, a somatic mutation in the USP8 gene was identified for the first time as frequently causing CD. Other studies have also identified somatic mutations causing CD in the BRAF, USP48, GNAS1, TP53, PIK3CA and possibly CABLES1 genes. It has been shown that some of these mutations lead to increased expression of the POMC gene (which encodes the precursor of ACTH).Regarding germline variants, it has been known for some time that mutations in the MEN1, RET, CDKN1B, AIP and PRKAR1A genes, wich are associated with multpile endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple neoplasia type 4, familial isolated pituitary adenoma and Carney complex, respectively, are conditions that predispose do Cushing's disease, albeit in a low frequency.Molecular differences between USP8-mutated corticotroph adenomas and other types of CD-causing tumors has been studied. Differential expression of PKA-Ca, HDAC, HSP90, p27, cyclin E, CABLES1 and p-CREB has been observed when USP8-mutated corticotrophs were compared to USP8 wild--type adenomas. It is possible, therefore, to argue that there are important differences, both in clinical phenotype and in the expression of several proteins according to the somatic mutation present in each type of corticotroph adenoma causing CD. In that sense, a detailed investigation of these differences may lead to identification of new therapeutic targets.The present study aims to evaluate the expression of proteins related to POMC transcription and to cell-ceylce regulation in CD, according to the somatic mutation detected in the corticotrophinomas. (AU)