Global DNA methylation and one-carbon metabolism gene polymorphisms and the risk of breast cancer in the Sister Study

Global decrease in DNA methylation is a common feature of cancer and is associated with genomic and chromosomal instability. Retrospective casecontrol studies have reported that cancer patients have lower global methylation levels in blood DNA than do controls. We used prospectively collected samples and a casecohort study design to examine global DNA methylation and incident breast cancer in 294 cases and a sample of 646 non-cases in the Sister Study, a study of 50 884 women aged 3574 years who had not been diagnosed with breast cancer at the time of blood draw. Global methylation in DNA from peripheral blood was assessed by pyrosequencing of the LINE-1 repetitive element. Quartiles of LINE-1 methylation levels were associated with the risk of breast cancer in a dose-dependent fashion (P, trend 0.002), with an increased risk observed among women in the lowest quartile compared with those in the highest quartile (hazard ratio 1.75; 95% confidence interval 1.19, 2.59). We also examined 22 polymorphisms in 10 one-carbon metabolism genes in relation to both LINE-1 methylation levels and breast cancer. We found three single-nucleotide polymorphisms in those genes associated with LINE-1 methylation: SLC19A1 (rs1051266); MTRR (rs10380) and MTHFR (rs1537514), one of which was also associated with breast cancer risk: MTHFR (rs1537514). PON1 (rs757158) was associated with breast cancer but not methylation.