Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis

Abstract

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.

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

“…In our study, we found that a distinct population of both ER þ and ER À tumours are associated with extensive methylation across the DMRs, more representative of a CpG island methylator phenotype (CIMP) 29 . Interestingly, a previous report describes the breast-CIMP (B-CIMP) group comprising solely ER þ tumours 16 ; however, our results show that coordinated hypermethylation can also occur in ER À disease. We also identified three distinct methylation clusters of TNBC tumours based on our DMRs.…”

“…We identified 308 genes affected by promoter hypermethylation and functional analysis revealed significant enrichment of genes and transcription factors involved in development and differentiation, as well as DNA binding, homeobox proteins and transcriptional regulation. Hypermethylation of homeobox genes has been previously reported in breast cancer and associated with disease progression and poor patient prognosis 15,16,34,35 . Genes encoding glycoproteins were also enriched in the functional analysis.…”

“…Recent studies have identified non-TNBC as more heavily methylated compared with TNBC 16 . In our study, we found that a distinct population of both ER þ and ER À tumours are associated with extensive methylation across the DMRs, more representative of a CpG island methylator phenotype (CIMP) 29 .…”

“…A number of studies have documented aberrant methylation events in breast carcinogenesis and identified specific DNA methylation biomarkers that have significant diagnostic and prognostic potential [9][10][11][12] . Several studies have also identified DNA methylation signatures that can distinguish between breast cancer subtypes [13][14][15][16] , and others that may be predictive of treatment response [17][18][19] .…”

Targeting the epigenome for treatment of cancer

“…Molecular classification of tumours could also guide treatment with broad-acting epigenetic drugs. DNMTis could be particularly useful in treating the subset of colorectal, brain and breast tumours that have a high degree of CpG island promoter hyper-methylation (Toyota et al, 1999;Noushmehr et al, 2010;Fang et al, 2011), which is now being clinically tested in colorectal cancer patients.…”