Chae Heejoon, Lee Sangseon, Nephew Kenneth P, Kim Sun
School of Informatics and Computing, Indiana University Bloomington, IN 47405, USA, Waterloo Road, Bloomington, IN, 47405, USA.
Department of Computer Science and Engineering, Seoul National University, Seoul, Republic of Korea.
BMC Syst Biol. 2016 Dec 23;10(Suppl 4):116. doi: 10.1186/s12918-016-0356-2.
Aberrant epigenetic modifications, including DNA methylation, are key regulators of gene activity in tumorigenesis. Breast cancer is a heterogeneous disease, and large-scale analyses indicate that tumor from normal and benign tissues, as well as molecular subtypes of breast cancer, can be distinguished based on their distinct genomic, transcriptomic, and epigenomic profiles. In this study, we used affinity-based methylation sequencing data in 30 breast cancer cell lines representing functionally distinct cancer subtypes to investigate methylation and mutation patterns at the whole genome level.
Our analysis revealed significant differences in CpG island (CpGI) shore methylation and mutation patterns among breast cancer subtypes. In particular, the basal-like B type, a highly aggressive form of the disease, displayed distinct CpGI shore hypomethylation patterns that were significantly associated with downstream gene regulation. We determined that mutation rates at CpG sites were highly correlated with DNA methylation status and observed distinct mutation rates among the breast cancer subtypes. These findings were validated by using targeted bisulfite sequencing of differentially expressed genes (n=85) among the cell lines.
Our results suggest that alterations in DNA methylation play critical roles in gene regulatory process as well as cytosine substitution rates at CpG sites in molecular subtypes of breast cancer.
包括DNA甲基化在内的异常表观遗传修饰是肿瘤发生过程中基因活性的关键调节因子。乳腺癌是一种异质性疾病，大规模分析表明，来自正常和良性组织的肿瘤以及乳腺癌的分子亚型，可以根据其独特的基因组、转录组和表观基因组特征加以区分。在本研究中，我们使用了代表功能不同癌症亚型的30个乳腺癌细胞系的基于亲和的甲基化测序数据，来研究全基因组水平的甲基化和突变模式。
我们的分析揭示了乳腺癌亚型之间CpG岛（CpGI）岸甲基化和突变模式的显著差异。特别是基底样B型，这是一种侵袭性很强的疾病形式，表现出明显的CpGI岸低甲基化模式，与下游基因调控显著相关。我们确定CpG位点的突变率与DNA甲基化状态高度相关，并在乳腺癌亚型中观察到不同的突变率。通过对细胞系中差异表达基因（n = 85）进行靶向亚硫酸氢盐测序，验证了这些发现。
我们的结果表明，DNA甲基化改变在乳腺癌分子亚型的基因调控过程以及CpG位点的胞嘧啶替代率中起着关键作用。
