Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in human breast cancer

Aberrant CpG island hypermethylation in gene promoter regions may be an important epigenetic event in human neoplasias, including breast cancer. Dietary and genetic factors that alter DNA methylation levels in normal and tumour tissues could therefore influence both the susceptibility to this disease and tumour phenotype, respectively. In the present study of 227 breast cancers, we investigated whether common polymorphisms in 6 key genes involved in methyl group metabolism (thymidylate synthase, methylene tetrahydrofolate reductase, cystathione β-synthase, DNA methyltransferase 3B, methylene tetrahydrofolate dehydrogenase, and methionine synthase) were associated with major pathological features of this disease or the frequency of CpG island hypermethylation. No associations were observed between any of the polymorphisms and patient age, tumour size, histological grade or patient outcome. However, tumours from patients who were homozygous for the methionine synthase A2756G polymorphism showed strikingly lower estrogen and progesterone hormone receptor concentrations compared to wild-type homozygotes. Moreover, patients who were homozygous for the methylene tetrahydrofolate dehydrogenase G1958A polymorphism showed a significantly higher frequency of tumour CpG island hypermethylation compared to wild-type homozygotes. Our results show that polymorphisms in two genes involved in methyl group metabolism are associated with hormone receptor content and DNA methylation frequency in breast cancer, however these observations are unlikely to be linked.