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.
Highlights
Common epigenetic changes in cancer include CpG island hypermethylation of gene promoters and genome-wide hypomethylation of non-coding genomic regions
There were no significant changes during the stepwise progression of breast cancer, Alu methylation tended to decrease during the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) (Figure 1A)
The median long interspersed nucleotide element-1 (LINE-1) methylation levels in normal breast, atypical ductal hyperplasia/flat epithelial atypia (ADH/flat epithelial atypia (FEA)), DCIS, and IBC were 64.1%, 61.6%, 59.9%, and 61.6%, respectively, being significantly different among the 4 groups (Kruskal-Wallis test; P = 0.008)
Summary
Common epigenetic changes in cancer include CpG island hypermethylation of gene promoters and genome-wide hypomethylation of non-coding genomic regions. While promoter CpG island hypermethylation is an alternative mechanism for inactivating tumor suppressor genes, resulting in their transcriptional silencing [1,2], genome-wide hypomethylation is associated with genomic instability and facilitates tumor progression [3,4]. Alu and long interspersed nucleotide element-1 (LINE-1) are major components of repetitive transposable DNA elements, constituting approximately 17% and 11% of the human genome [14]. Because of their high frequencies in the genome, Alu and LINE-1 methylation status serve as a useful surrogate marker for genome-wide methylation status. In breast cancer, studies on changes of Alu and LINE-1 methylation status during the multistep progression of breast cancer have been rare
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