Abstract
IntroductionDNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs). In cancer cells, global hypomethylation of the genome as a whole and regional hypermethylation of CpG islands have been reported. Four groups of DNMTs have been identified: DNMT1, DNMT2 (TRDMT1), DNMT3A and DNMT3B. DNMT2 uses the catalytic mechanism of DNMTs, but does in fact methylate RNA. Little is known about the significance of these genes in human breast cancer. In the study presented herein, we analyzed five distinct DNMT single SNPs with regard to potential associations with breast cancer risk.Case descriptionIn this study, we genotyped 221 female Caucasian breast cancer patients and 221 female Caucasian healthy controls, and we used five allele-specific real-time polymerase chain reaction (qPCR) assays. We selected one locus within the DNMT1 gene and two loci within the DNMT3A and DNMT3B genes, respectively. Statistics were calculated using the chi-squared and Fisher’s exact tests, and correlated with clinical parameters such as age, diagnosis, histology, TNM stage, hormonal receptor status, human epidermal growth factor receptor 2 (HER2) status, response to treatment and survival. Statistically significant results were obtained for correlations with the DNMT1 gene.Discussion and EvaluationFive genomic loci within the DNMT1, DNMT3A and DNMT3B genes were assessed. Statistical significance (P = 0.030) was identified for DNMT1 SNP (A201G, rs2228612): six women within the control group were GG homozygous (variant), while this mutation was absent in the breast cancer group.ConclusionsWe conclude that women with the DNMT1 SNP (A201G, rs2228612) GG homozygous genotype (variant) have a lower risk of developing breast cancer compared to heterozygous or wildtype genotypes. To date, alterations within the DNMT1 gene have not been reported to be associated with cancer in the Caucasian population.
Highlights
DNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs)
We conclude that women with the DNMT1 Single nucleotide polymorphism (SNP) (A201G, rs2228612) GG homozygous genotype have a lower risk of developing breast cancer compared to heterozygous or wildtype genotypes
Alterations within the DNMT1 gene have not been reported to be associated with cancer in the Caucasian population
Summary
DNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs). Global hypomethylation of the genome as a whole and regional hypermethylation of CpG islands have been reported. Histone modifications take place in eukaryotic cells, while DNA methylation takes place in both eukaryotic and prokaryotic cells. Both are relevant key elements within the transcriptional regulatory machinery [3]. Promoter CpG islands are typically hypermethylated in many types of cancers, which can lead to transcriptional silencing of the corresponding genes [5,6]. The hypermethylation of gene promoters or a hypomethylation of various parts of the genome can contribute to the development of cellular malignancy or autoimmune disease [7]
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