We observed lower levels of global methylation in WBC DNA in girls with a family history of breast cancer than in girls without a family history, although this association was only statistically significant with global DNA methylation as measured by Alu
MethyLight and LINE1
pyrosequencing. In utero exposures and early-life factors have been associated with increased risk of breast cancer.11,12,14
Changes in DNA methylation level may be one mechanism linking early-life exposures to adult health.10,16,21
We have previously reported that in utero exposure to maternal cigarette smoking and other risk factors across the life course, such as age at menarche, birth length and pregnancy history, were associated with adult levels of methylation measured in the peripheral blood of women.16
Here we observed an inverse association between LINE1
methylation and age at menarche and breast development (Tanner score). The association with Tanner staging remained after adjusting for age, family history and body mass index. The molecular mechanisms by which pubertal status may be associated with methylation patterns needs to be further investigated in larger samples.
Studies of global DNA methylation patterns in families have found positive correlations in DNA methylation levels within families pointing to shared environment and/or genetics in explaining DNA methylation patterns.8
However, twin studies also support greater differences in DNA methylation patterns as twins age suggesting a role for the environment in explaining differences even within families.6
Lower 5-methyldeoxycytosine (m5C) in leukocyte DNA was observed in breast cancer patients compared with cancer-free controls, and the association between global demethylation and breast cancer risk was more pronounced among women with a family history of breast cancer.2
We found that girls with a family history of breast cancer had lower methylation levels in Alu
elements compared with girls without a family history; the association with Alu
and family history remained after further adjusting for Tanner stage and BMI.
DNA methylation of centromeric repeats and repetitive sequences accounts for the bulk of global DNA methylation levels in the genome. LINE sequences account for at least 34% of the human genome and Alu repeats comprise at least 10%.22,23
Loss of DNA methylation in these sequences is thought to cause chromosomal instability, reactivation of transposable elements and loss of imprinting resulting in the initiation of carcinogenesis.24
If replicated in much larger studies, our study suggests that DNA methylation levels may differ between families with and without breast cancer, and that these differences may be observed early in life. Prospective studies measuring global DNA methylation over time within the same individuals are needed in order to understand the potential role of environmental factors in altering global DNA methylation patterns, even early in life.