title: Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.
abstract: Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs) and the hypomethylation of the megabase-sized partially methylated domains (PMDs) are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI) was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma) dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Lin
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Dow-Tien
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Su
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ching
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Swee-Chuan
authors.initials: SC
authors.lastname: Ng
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsiao-Tan
authors.initials: HT
authors.lastname: Chen
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Mei-Chen
authors.initials: MC
authors.lastname: Lee
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Chen
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Hui
authors.initials: SH
authors.lastname: Suen
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Chen
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tze-Tze
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan; Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chuan-Hsiung
authors.initials: CH
authors.lastname: Chang
authors.affiliation: VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Hsu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D052138:Genes, Neoplasm; D006801:Humans; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D049951:X Chromosome Inactivation