Landscape of genome-wide age-related DNA methylation in breast tissue
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Min-Ae Song1,2, Theodore M. Brasky1, Daniel Y. Weng1, Joseph P. McElroy1,3, Catalin Marian4, Michael J. Higgins5, Christine Ambrosone6, Scott L. Spear7, Adana A. Llanos8, Bhaskar V.S. Kallakury9, Jo L. Freudenheim10 and Peter G. Shields1
1Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, USA
2College of Public Health, The Ohio State University, Columbus, OH, USA
3Center for Biostatistics and Department of Bioinformatics, The Ohio State University, Columbus, OH, USA
4Biochemistry and Pharmacology Department, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
5Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
6Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
7Department of Plastic Surgery, Georgetown University, Washington, DC, USA
8Department of Epidemiology, Rutgers School of Public Health and Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
9Department of Pathology, Georgetown University, Washington, DC, USA
10Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA
Peter G. Shields, email: [email protected]
Keywords: genome-wide DNA methylation; age; breast; normal; cancer
Received: March 08, 2017 Accepted: November 06, 2017 Published: November 29, 2017
Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross-sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm’s. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA-BRCA data were used for replication. 1,214 aDNAm’s were identified; 97% with increased methylation, and all on autosomes. Sites with increased methylation were predominantly in CpG lslands and non-enhancers. aDNAm’s with decreased methylation were generally located in intergenic regions, non-CpG Islands, and enhancers. Of the aDNAm’s identified, 650 are known to be involved in cancer, including ESR1 and beta-estradiol responsive genes. Expression of DNMT3A was positively associated with age. Two aDNAm’s showed borderline significant associations with DNMT3A expression; KRR1 (OR 6.57, 95% CI: 2.51–17.23) and DHRS12 (OR 6.08, 95% CI: 2.33–15.86). A subset of aDNAm’s co-localized within vulnerable regions for somatic mutations in cancers including breast cancer. Expression of C19orf48 was inversely and significantly correlated with its methylation level. In the TCGA dataset, 84% and 64% of the previously identified aDNAm’s were correlated with age in both normal-adjacent and tumor breast tissues, with differential associations by histological subtype. Given the similarity of findings in the breast tissues of healthy women and breast tumors, aDNAm’s may be one pathway for increased breast cancer risk with age.
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