Investigation of MLH1, MGMT, CDKN2A, and RASSF1A Gene Methylation in Thymomas From Patients With Myasthenia Gravis

Fabio Coppedè; Roberta Ricciardi; Angela Lopomo; Andrea Stoccoro; Anna De Rosa; Melania Guida; Loredana Petrucci; Michelangelo Maestri; Marco Lucchi; Lucia Migliore

doi:10.3389/fnmol.2020.567676

Investigation of MLH1, MGMT, CDKN2A, and RASSF1A Gene Methylation in Thymomas From Patients With Myasthenia Gravis

Front Mol Neurosci. 2020 Oct 23:13:567676. doi: 10.3389/fnmol.2020.567676. eCollection 2020.

Authors

Affiliations

¹ Department of Translational Research and of New Surgical and Medical Technologies, Medical Genetics Laboratory, University of Pisa, Pisa, Italy.
² Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy.
³ Division of Thoracic Surgery, Cardiothoracic and Vascular Surgery Department, Pisa University Hospital, Pisa, Italy.
⁴ Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.

Abstract

A feature of thymomas is their frequent association with myasthenia gravis (MG), an autoimmune disease characterized by the production of autoantibodies directed to different targets at the neuromuscular junction. Indeed, almost 30-40% of thymomas are found in patients with a type of MG termed thymoma-associated MG (TAMG). Recent studies suggest that TAMG-associated thymomas could represent a molecularly distinct subtype of thymic epithelial tumors (TETs), but few data are still available concerning the epigenetic modifications occurring in TAMG tissues. The promoter methylation levels of DNA repair (MLH1 and MGMT) and tumor suppressor genes (CDKN2A and RASSF1A) have been frequently investigated in TETs, but methylation data in TAMG tissues are scarce and controversial. To further address this issue, we investigated MLH1, MGMT, CDKN2A, and RASSF1A methylation levels in blood samples and surgically resected thymomas from 69 patients with TAMG and in the adjacent normal thymus available from 44 of them. Promoter methylation levels of MLH1, MGMT, CDKN2A, and RASSF1A genes were not increased in cancer with respect to healthy tissues and did not correlate with the histological or pathological features of the tumor or with the MG symptoms. The present study suggests that hypermethylation of these genes is not frequent in TAMG tissues.

Keywords: CDKN2A; DNA methylation; MGMT; MLH1; RASSF1A; epigenetics; myasthenia gravis; thymoma.