Abstract
Simple SummaryCancers are characterized by accumulation of genetic mutations in key cell cycle regulators that alter or disable the function of these genes. Such mutations can be inherited or arise spontaneously during the life of the individual. The MEN1 gene prevents uncontrolled cell division and it is considered a tumor suppressor. Inherited MEN1 mutations are associated with certain parathyroid and pancreatic syndromes while spontaneous mutations have been detected in cancer cells. We investigated whether inherited mutations appear in cancer cells which would suggest that patients with parathyroid and pancreatic syndromes have a predisposition to develop cancer. We find a weak correlation between the spectrum of inherited mutations and those appearing spontaneously. Thus, inherited MEN1 mutations may not be a good predictor of tumorigenesis.MENIN is a scaffold protein encoded by the MEN1 gene that functions in multiple biological processes, including cell proliferation, migration, gene expression, and DNA damage repair. MEN1 is a tumor suppressor gene, and mutations that disrupts MEN1 function are common to many tumor types. Mutations within MEN1 may also be inherited (germline). Many of these inherited mutations are associated with a number of pathogenic syndromes of the parathyroid and pancreas, and some also predispose patients to hyperplasia. In this study, we cataloged the reported germline mutations from the ClinVar database and compared them with the somatic mutations detected in cancers from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. We then used statistical software to determine the probability of mutations being pathogenic or driver. Our data show that many confirmed germline mutations do not appear in tumor samples. Thus, most mutations that disable MEN1 function in tumors are somatic in nature. Furthermore, of the germline mutations that do appear in tumors, only a fraction has the potential to be pathogenic or driver mutations.
Highlights
The tumor suppressor gene MEN1 encodes MENIN, a scaffold protein with diverse functions in cell cycle regulation, DNA repair, and gene expression [1,2]
We showed that only a fraction of inherited MEN1 aberrations appear as somatic mutations in tumors
Germline MEN1 mutations contribute to the clinical pathologies of the parathyroid, thyroid, and pancreatic syndromes, we find that very few contribute to neoplasia and cancer
Summary
The tumor suppressor gene MEN1 encodes MENIN, a scaffold protein with diverse functions in cell cycle regulation, DNA repair, and gene expression [1,2]. 2020, 12, x that itCancers contains four major domains: an N-terminal domain (NTD), two middle thumb and palm domains, and a C-terminus Fingers domain [3,4] (Figure 1A). A central cavity in the thumb and palm that it contains four major domains: an N-terminal domain (NTD), two middle thumb and palm domains contains. ASuch central cavityare in the thumb and palm and inter-molecular interactions [5]. MENIN interaction with various domains contains several TPR (tetracopeptide repeat) motifs. Such motifs are involved in intra- and proteins. Several other structural motifs have been identified and are discussed elsewhere inter-molecular interactions [5] and have been proposed to facilitate MENIN interaction with various[3,4]
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