Association of the DNMT3B -579G>T Polymorphism with Risk of Thymomas in Patients with Myasthenia Gravis

Abstract

Increasing evidence suggests a contribution of epigenetic processes in promoting cancer and autoimmunity. Myasthenia gravis (MG) is an autoimmune disease mediated, in approximately 80% of the patients, by antibodies against the nicotinic acetylcholine receptor (AChR+). Moreover, epithelial tumours (thymomas) are present in about 10-20% of the patients, and there is indication that changes in DNA methylation might contribute to the risk and progression of thymomas. However, the role of epigenetics in MG is still not completely clarified. In the present study we investigated if a common polymorphism (-579G>T: rs1569686) in the promoter of the DNMT3B gene coding for the DNA methyltransferase 3B, an enzyme that mediates DNA methylation, increases the risk to develop MG or MG-associated thymomas. The study polymorphism was selected based on recent reports and a literature meta-analysis suggesting association with increased risk of various types of cancer. We screened 324 AChR+ MG patients (140 males and 184 females, mean age 56.0 ± 16.5 years) and 735 healthy matched controls (294 males and 441 females, mean age 57.3 ± 15.6 years). 94 of the total MG patients had a thymoma. While there was no association with the whole cohort of MG patients, we found a statistically significant association of the DNMT3B -579T allele (OR = 1.51; 95% CI=1.1-2.1, P = 0.01) and the TT homozygous genotype (OR = 2.59; 95% CI=1.4-4.9, P = 0.006) with the risk of thymoma. No association was observed in MG patients without thymoma, even after stratification into clinical subtypes. Present results suggest that the DNMT3B -579T allele might contribute to the risk of developing thymoma in MG patients, particularly in homozygous TT subjects.

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

“…A functional role of this gene in thymic epithelial tumors emerged from studies that focused on mutation analysis, revealing that DNMT3A is one the most frequently mutated genes in thymic carcinoma [34], and that the mutation p.G728D is associated with B3 thymomas [35]. Similarly, a SNP in the promoter of DNMT3B , namely −579G>T, was associated with TAMG [36], overall suggesting a contribution of de novo DNMTs in thymomas.…”

DNMT3B Functions: Novel Insights From Human Disease

“…The onset of the intestinal Hirschsprung disease was associated with the overexpression of recognized DNMT3B target genes in enteric nervous system development ( Torroglosa et al, 2017 ; Villalba-Benito et al, 2017 ). Moreover, a promoter polymorphism (-579G > T) was associated with idiopathic thrombocytopenic purpura ( Zhao et al, 2009 ) and with a higher risk of thymomas in patients with myasthenia gravis ( Coppede et al, 2013 ).…”

Complicating autoimmune diseases in myasthenia gravis: a review

“…Risk of thymoma in MG is associated with the TT homozygous genotype and the DNMT3B-579T allele [ 56 ]. This genotype does not occur with increased frequency in MG patients without thymoma, even after stratification into MG subgroups [ 57 ].…”