title: Alu and LINE-1 hypomethylation is associated with HER2 enriched subtype of breast cancer.
abstract: The changes in DNA methylation status in cancer cells are characterized by hypermethylation of promoter CpG islands and diffuse genomic hypomethylation. Alu and long interspersed nucleotide element-1 (LINE-1) are non-coding genomic repetitive sequences and methylation of these elements can be used as a surrogate marker for genome-wide methylation status. This study was designed to evaluate the changes of Alu and LINE-1 hypomethylation during breast cancer progression from normal to pre-invasive lesions and invasive breast cancer (IBC), and their relationship with characteristics of IBC. We analyzed the methylation status of Alu and LINE-1 in 145 cases of breast samples including normal breast tissue, atypical ductal hyperplasia/flat epithelial atypia (ADH/FEA), ductal carcinoma in situ (DCIS) and IBC, and another set of 129 cases of IBC by pyrosequencing. Alu methylation showed no significant changes during multistep progression of breast cancer, although it tended to decrease during the transition from DCIS to IBC. In contrast, LINE-1 methylation significantly decreased from normal to ADH/FEA, while it was similar in ADH/FEA, DCIS and IBC. In IBC, Alu hypomethylation correlated with negative estrogen receptor (ER) status, and LINE-1 hypomethylation was associated with negative ER status, ERBB2 (HER2) amplification and p53 overexpression. Alu and LINE-1 methylation status was significantly different between breast cancer subtypes, and the HER2 enriched subtype had lowest methylation levels. In survival analyses, low Alu methylation status tended to be associated with poor disease-free survival of the patients. Our findings suggest that LINE-1 hypomethylation is an early event and Alu hypomethylation is probably a late event during breast cancer progression, and prominent hypomethylation of Alu and LINE-1 in HER2 enriched subtype may be related to chromosomal instability of this specific subtype.
authors: Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea; Department of Pathology, Seoul National University Bundang Hospital, Bundang-gu, Seongnam, Gyeonggi, Korea.
authors: So Yeon
authors: SY
authors: Park
authors: Department of Pathology, Seoul National University Bundang Hospital, Bundang-gu, Seongnam, Gyeonggi, Korea.
authors: An Na
authors: AN
authors: Seo
authors: Department of Pathology, Seoul National University Bundang Hospital, Bundang-gu, Seongnam, Gyeonggi, Korea.
authors: Hae Yoen
authors: HY
authors: Jung
authors: Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea.
authors: Jae Moon
authors: JM
authors: Gwak
authors: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea.
authors: Namhee
authors: N
authors: Jung
authors: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea.
authors: Nam-Yun
authors: NY
authors: Cho
authors: Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea; Laboratory of Epigenetics, Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea.
authors: Gyeong Hoon
authors: GH
authors: Kang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020087:Alu Elements; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases