title: Age-related DNA methylation in normal breast tissue and its relationship with invasive breast tumor methylation.
abstract: Age is a key risk factor for breast cancer and epigenetic alterations may contribute to age-related increases in breast cancer risk, though the relation of age-related methylation in normal breast tissues with altered methylation in breast tumors is unclear. We investigated the relation of age with DNA methylation in normal breast tissues genome-wide using two data sets from the Gene Expression Omnibus (GEO) database (GSE32393 and GSE31979). We validated our observations in an independent set of normal breast tissues, examined age-related methylation in normal breast for enrichment of genomic features, and compared age-related methylation in normal tissue with methylation alterations in breast tumors. Between the two array-based methylation data sets, there were 204 CpG loci with significant (P<0.05) and consistent age-related methylation, 97% of which were increases in methylation. Our validation sets confirmed the direction of age-related DNA methylation changes in all measured regions. Among the 204 age-related CpG loci, we observed a significant enrichment for CpG islands (P = 8.7E-6) and polycomb group protein target genes (P = 0.03). In addition, 24 of the 204 CpGs with age-related methylation in normal breast were significantly differentially methylated between normal and breast tumor tissues. We identified consistent age-related methylation changes in normal breast tissue that are further altered in breast tumors and may represent early events contributing to breast carcinogenesis. This work identifies age-related methylation in normal breast tissue and begins to deconstruct the contribution of aging to epigenetic alterations present in breast tumors.
authors.affiliation: Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Geisel School of Medicine at Dartmouth; Hanover, NH USA; Department of Pharmacology and Toxicology; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Johnson
authors.affiliation: Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.affiliation: Department of Genetics; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Geisel School of Medicine at Dartmouth; Hanover, NH USA; Department of Pharmacology and Toxicology; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008875:Middle Aged; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D063146:Polycomb-Group Proteins
keywords: Breast; aging; array; cancer; methylation; normal