DNA Methylation in Breast Cancers: Differences based on Estrogen Receptor Status and Recurrence

DNA methylation plays a role in the etiology of primary breast cancers. We analyzed paired primary and second breast tumors to elucidate the role of methylation in recurrence. Methylation profiles from paired primary and second breast tumors of 23 women were assessed using the HumanMethylation450 BeadChip. Twelve women had ERpos primary and second tumors, five had estrogen receptor negative (ERneg) primary and second tumors, and six had an ERpos primary tumor but an ERneg second tumor. Stratifying tumors by occurrence revealed that the greater methylation previously associated with ERpos tumors, is more pronounced in primary tumors than in second tumors. Further, ERneg second tumors are more methylated than ERpos second tumors among women who had ERpos primary tumors. Pathway analyses using gene lists generated from comparisons of methylation in ERpos primary tumors from the paired sets with ERpos tumors from 6 women without recurrences, identified differences between groups based on the ER status of the second tumor. Hypermethylated genes of significantly enriched pathways were differentially associated with survival. DNA methylation profiles of ERpos primary breast tumors support the development and use of tumor methylation profiles for stratifying women with breast cancer both for prognosis and therapy. Primary tumors (referred to as first tumors) were matched to a second tumor from the same woman in either the ipsilateral or contralateral breast. HumanMethylation450 Bead Chip (HM450 BC) data were obtained for 46 paired tumors and assigned group labels for ease of reading as follows: 12 tumor pairs from women with ERpos first (A1) and ERpos second tumors (A2), 5 tumor pairs from women with ERneg first tumors (B1) and ERneg second tumors (B2), and 6 tumor pairs from women with ERpos first tumors (C1) and ERneg second tumors (C2). Additionally, 6 ERpos tumors from women with no breast cancer recurrence after a 7-year follow up period were included for methylation analysis.