The biological basis and function of GNAS mutation in pseudomyxoma peritonei: a review

Abstract

Purpose Pseudomyxoma peritonei (PMP) is a rare clinical malignancy syndrome characterized by the uncontrollable accumulation of copious mucinous ascites in the peritoneal cavity, resulting in “jelly belly”. The mechanism of tumor progression and mucin hypersecretion remains largely unknown, but GNAS mutation is a promising contributor. This review is to systemically summarize the biological background and variant features of GNAS , as well as the impacts of GNAS mutations on mucin expression, tumor cell proliferation, clinical-pathological characteristics, and prognosis of PMP. Methods NCBI PubMed database (in English) and WAN FANG DATA (in Chinese) were used for literature search. And NCBI Gene and Protein databases, Ensembl Genome Browser, COSMIC, UniProt, and RCSB PDB database were used for gene and protein review. Results GNAS encodes guanine nucleotide-binding protein α subunit (Gsα). The mutation sites of GNAS mutation in PMP are relatively stable, usually at Chr20: 57,484,420 (base pair: C-G) and Chr20: 57,484,421 (base pair: G-C). Typical GNAS mutation results in the reduction of GTP enzyme activity in Gsα, causing failure to hydrolyze GTP and release phosphoric acid, and eventually the continuous binding of GTP to Gsα. The activated Gsα could thus continuously promote mucin secretion through stimulating the cAMP-PKA signaling pathway, which is a possible mechanism leading to elevated mucin secretion in PMP. Conclusion GNAS mutation is one of the most important molecular biological features in PMP, with major functions to promote mucin hypersecretion.

Discovery of Novel Variants on the CHD7 Gene: A Case Series of CHARGE Syndrome

“…253C > T (p.Q85*), C. 780del (p.S261Lfs*44), C. 7252C > T (p.R2418*), and C. 5428C > T (P.ARg1810ter) were mainly reported in molecular studies of gene mutations, without specific descriptions of clinical phenotypes (Koenighofer et al, 2015;Zaki et al, 2018;Shotelersuk et al, 2020; Lee et al, 2021). C. 6018DUP (p.S2007Ifs*2) was reported in a study related to endocrine and olfactory, but there was no more phenotypic description (Lin et al, 2020). In this study, the phenotype of C.4667dupC (P. r1557KFS *16) was basically consistent with previous reports.…”

Autoantibody to GNAS in Early Detection of Hepatocellular Carcinoma: A Large-Scale Sample Study Combined with Verification in Serial Sera from HCC Patients

“…GNAS , as one of the most common mutated genes, has been shown to be closely related to cancers. Its activating mutations were associated with uncontrolled intracellular cAMP accumulation leading to cellular proliferation and tumor formation through the stimulation of different signaling pathways [ 42 , 43 ]. It was found in Nault’s study that the activation of signaling pathways caused by GNAS activating mutations and the inflammatory effect of STAT3 activation may have synergistic effects in hepatocellular carcinogenesis [ 44 ].…”

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

“…The ovarian site had increased expression of the progenitor state marker SOX4 . The three lesions also differed in their expression of GNAS , a frequently mutated gene in PMP that regulates mucin production [59].…”