title: Normal cell-type epigenetics and breast cancer classification: a case study of cell mixture-adjusted analysis of DNA methylation data from tumors.
abstract: Historically, breast cancer classification has relied on prognostic subtypes. Thus, unlike hematopoietic cancers, breast tumor classification lacks phylogenetic rationale. The feasibility of phylogenetic classification of breast tumors has recently been demonstrated based on estrogen receptor (ER), androgen receptor (AR), vitamin D receptor (VDR) and Keratin 5 expression. Four hormonal states (HR0-3) comprising 11 cellular subtypes of breast cells have been proposed. This classification scheme has been shown to have relevance to clinical prognosis. We examine the implications of such phylogenetic classification on DNA methylation of both breast tumors and normal breast tissues by applying recently developed deconvolution algorithms to three DNA methylation data sets archived on Gene Expression Omnibus. We propose that breast tumors arising from a particular cell-of-origin essentially magnify the epigenetic state of their original cell type. We demonstrate that DNA methylation of tumors manifests patterns consistent with cell-specific epigenetic states, that these states correspond roughly to previously posited normal breast cell types, and that estimates of proportions of the underlying cell types are predictive of tumor phenotypes. Taken together, these findings suggest that the epigenetics of breast tumors is ultimately based on the underlying phylogeny of normal breast tissue.
authors.affiliation: School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA.
authors.forename: Eugene Andrés
authors.initials: EA
authors.lastname: Houseman
authors.affiliation: Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL, USA.
authors.forename: Tan A
authors.initials: TA
authors.lastname: Ince
keywords: DNA methylation; EWAS; androgen receptor; cell composition; deconvolution; estrogen receptor