Multiple tumours of different lineages likely related to a DNMT3A pathogenic R688H variant

Introduction The relationship between epigenetic modifications that influence gene regulation, such as histone deacetylation, microRNA regulation and DNA methylation, and human diseases has become increasingly recognised. Dysregulation of DNA methylation has been implicated in genomic imprinting and tumourigenesis. Previous studies identified several epigenetic modifier genes that directly cause genomic DNA (gDNA) methylation such as DNA methyltransferases (DNMTs). DNMT aberrations usually affect genome-wide methylation profiles, deactivating many tumour suppressor genes by methylation of their promoters. In this study, we describe a unique case with several tumours of different lineages, likely caused by a germline pathogenic DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) variant.Methods We evaluated a middle-aged female who suffered from multiple metachronous and synchronous tumours, mostly benign, including subcutaneous lipomas and mesenchymal tumours, multinodular goitre, a parathyroid adenoma, a complex meningioma, a benign breast tumour, bilateral non-functioning adrenal nodules, hepatic and renal cysts and a pancreatic neuroendocrine tumour. The patient’s gDNA was subjected to whole-exome sequencing and strict bioinformatics analysis. The possible effect of the variant was investigated using multiple in-silico analysis tools and protein three-dimensional modelling.Results A heterozygous missense DNMT3A variant (c.2063G>A, p.R688H) was identified. The identified variant was Sanger sequenced in all available patient’s samples. Protein modelling strongly supports the pathogenic role of this variant in the development of the several tumours that this patient had.Conclusions We report the c.2063G>A DNMT3A variant as a potential cause of multiple unrelated tumours. This is the first report of such a case and one of a few reports of DNMT3A germline variants causing tumourigenesis.