Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis

Breast cancer methylomes contribute to metastatic potential, modulate the metastasis transcriptome, and predict disease outcome. Meditating on Breast Cancer People of diverse faiths and backgrounds have gained new mindsets when contemplating “Om” (or Aum)—a meditation symbol that represents the universe in its entirety. The concept of examining existence from a global perspective has begun to take hold in cancer research as well. Indeed, researchers have created their own “omes”: the genome, the transcriptome, the proteome. Here, Fang et al. examine the methylome of breast cancer and find a signature that may predict metastasis. The authors used genome-wide analysis to examine methylome signatures in breast cancers with various metastatic behaviors and found a signature that was associated with low metastatic risk and improved rates of survival. This breast CpG island methylator phenotype (B-CIMP) tracked with reduced metastasis independently of other breast cancer markers [such as estrogen receptor/progesterone receptor (ER/PR) and human epidermal growth factor receptor 2 (HER2) status] and was shared by multiple human malignancies, including glioma and colon cancer. However, altered methylation status may not just be a marker of metastasis: Methylation of B-CIMP signature genes correlated with transcriptional diversity among breast cancers with different prognoses. Thus, the B-CIMP phenotype may thus play a mechanistic role in metastatic risk, and future meditation on the methylome may improve breast cancer prognosis and therapy. Cancer-specific alterations in DNA methylation are hallmarks of human malignancies; however, the nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Groups of breast tumors were characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating a breast CpG island methylator phenotype (B-CIMP). The B-CIMP provided a distinct epigenomic profile and was a strong determinant of metastatic potential. Specifically, the presence of the B-CIMP in tumors was associated with low metastatic risk and survival, and the absence of the B-CIMP was associated with high metastatic risk and death. B-CIMP loci were highly enriched for genes that make up the metastasis transcriptome. Methylation at B-CIMP genes accounted for much of the transcriptomal diversity between breast cancers of varying prognosis, indicating a fundamental epigenomic contribution to metastasis. Comparison of the loci affected by the B-CIMP with those affected by the hypermethylator phenotype in glioma and colon cancer revealed that the CIMP signature was shared by multiple human malignancies. Our data provide a unifying epigenomic framework linking breast cancers with varying outcome and transcriptomic changes underlying metastasis. These findings significantly enhance our understanding of breast cancer oncogenesis and aid the development of new prognostic biomarkers for this common malignancy.