title: 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.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors: Fang
authors: F
authors: Fang
authors: Sevin
authors: S
authors: Turcan
authors: Andreas
authors: A
authors: Rimner
authors: Andrew
authors: A
authors: Kaufman
authors: Dilip
authors: D
authors: Giri
authors: Luc G T
authors: LG
authors: Morris
authors: Ronglai
authors: R
authors: Shen
authors: Venkatraman
authors: V
authors: Seshan
authors: Qianxing
authors: Q
authors: Mo
authors: Adriana
authors: A
authors: Heguy
authors: Stephen B
authors: SB
authors: Baylin
authors: Nita
authors: N
authors: Ahuja
authors: Agnes
authors: A
authors: Viale
authors: Joan
authors: J
authors: Massague
authors: Larry
authors: L
authors: Norton
authors: Linda T
authors: LT
authors: Vahdat
authors: Mary Ellen
authors: ME
authors: Moynahan
authors: Timothy A
authors: TA
authors: Chan
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D013058:Mass Spectrometry; D046228:Microarray Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor