Epigenetic regulation of imprinted genes enables monoallelic expression according to parental origin, and its disruption is implicated in many
cancers and developmental disorders. The expression of
hormone receptors is significant in
breast cancer because they are indicators of
cancer cell growth rate and determine response to endocrine
therapies. We investigated the frequency of aberrant events and variation in DNA methylation at nine imprinted sites in invasive
breast cancer and examined the association with
estrogen and
progesterone receptor status. Breast tissue and blood from patients with invasive
breast cancer (n = 38) and benign
breast disease (n = 30) were compared with those from healthy individuals (n = 36), matched with the
cancer patients by age at diagnosis, ethnicity, body mass index, menopausal status and familial history of
cancer. DNA methylation and allele-specific expression were analyzed by pyrosequencing.
Tumor-specific methylation changes at IGF2 DMR2 were observed in 59% of
cancer patients, IGF2 DMR0 in 38%, DIRAS3 DMR in 36%, GRB10 ICR in 23%, PEG3 DMR in 21%, MEST ICR in 19%, H19 ICR in 18%, KvDMR in 8% and
SNRPN/SNURF ICR in 4%. Variation in methylation was significantly greater in breast tissue from
cancer patients compared with that in healthy individuals and benign
breast disease. Aberrant methylation of three or more sites was significantly associated with negative
estrogen-alpha (Fisher's exact test, p = 0.02) and
progesterone-A (p = 0.02) receptor status. Aberrant events and increased variation in imprinted gene DNA methylation, therefore, seem to be frequent in invasive
breast cancer and are associated with negative
estrogen and
progesterone receptor status, without loss of monoallelic expression.