Subtype-specific CpG island shore methylation and mutation patterns in 30 breast cancer cell lines.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
School of Informatics and Computing, Indiana University Bloomington, IN 47405, USA, Waterloo Road, Bloomington, IN, 47405, USA.
Heejoon
H
Chae
Department of Computer Science and Engineering, Seoul National University, Seoul, Republic of Korea.
Sangseon
S
Lee
Indiana University School of Medicine, Department of Cellular and Integrative Physiology, Medical Sciences Program, Bloomington, USA.
Kenneth P
KP
Nephew
Department of Computer Science and Engineering, Seoul National University, Seoul, Republic of Korea. sunkim.bioinfo@snu.ac.kr.|Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea. sunkim.bioinfo@snu.ac.kr.|Bioinformatics Institute, Seoul National University, Seoul, Republic of Korea. sunkim.bioinfo@snu.ac.kr.
Sun
S
Kim
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D023281:Genomics; D006801:Humans; D009154:Mutation
Breast cancer; CpGI shore; DNA methylation; Mutation; Subtype