title: Remodeling of the methylation landscape in breast cancer metastasis.
abstract: The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Marsha
authors.initials: M
authors.lastname: Reyngold
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kasthuri
authors.initials: K
authors.lastname: Kannan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Logan A
authors.initials: LA
authors.lastname: Walsh
authors.affiliation: Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Pathology Core, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Marija
authors.initials: M
authors.lastname: Drobnjak
authors.affiliation: Department of Medicine, Weill Cornell Medical Center, New York, New York, United States of America.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D005260:Female; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics
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