Evaluation of Nonsynonymous Single Nucleotide Polymorphisms in the DNMT1 Gene Associated With Gastric Cancer by an In-Silico Approach

The human DNMT1 (NCBI GENE ID: 1786) gene encodes a DNA methyltransferase-1 which is also termed as maintenance methyltranferase. The DNMT1 (DNA Methyl Tranferase-1) gene plays a substantial role in aberrant DNA methylation in carcinogenesis. Over-expression (Increased activity) and polymorphisms within the DNMT1 gene is allied with a multiplied risk of gastric cancer. Most deleterious non synonymous single nucleotide polymorphisms in the coding region of the DNMT1 gene were investigated using SNP databases, and detected nonsynonymous variants were analyzed in silica from the standpoint of relevant protein function and stability by PolyPhen-2, SIFT, PROVEAN and MUpro, I-Mutant2.0 tools respectively. A sum of 93 nonsynonymous SNPs comprising of 92 missense variations and one frameshift variations were found in the DNMT1 gene. 10 of the 92 nnissense variants were predicted to be damaging or deleterious by three different software Programs PolyPhen-2, SIFT, and PROVEAN, and 37 of them were predicted to be less stable using I Mutant 2.0 and MUpro software. Total 5 variants namely c.4324C>T (p.Arg1442Trp), c.3913C>T (p.Arg1305Cys), c.3223C>T (p.Arg1075Cys) c.3097C>T (p.Arg1033Trp), c.1531T>C (p.Tyr511His) out of 92 missense variants were predicted to be both deleterious and reduced protein stability.Additionally, one frameshift variant (rs35600922) c.3475_3476insG (p.Asp1159Gly) was predicted to be both deleterious and less stable. Deleterious variants of DNMT1' gene with reduced protein stability were suggested that a subset of nonsynonymous SNPs in the DNMT1 gene might be associated with risk of cancer, including gastric cancer.