title: A methyl-deviator epigenotype of estrogen receptor-positive breast carcinoma is associated with malignant biology.
abstract: We broadly profiled DNA methylation in breast cancers (n = 351) and benign parenchyma (n = 47) for correspondence with disease phenotype, using FFPE diagnostic surgical pathology specimens. Exploratory analysis revealed a distinctive primary invasive carcinoma subclass featuring extreme global methylation deviation. Subsequently, we tested the correlation between methylation remodeling pervasiveness and malignant biological features. A methyl deviation index (MDI) was calculated for each lesion relative to terminal ductal-lobular unit baseline, and group comparisons revealed that high-grade and short-survival estrogen receptor-positive (ER(+)) cancers manifest a significantly higher MDI than low-grade and long-survival ER(+) cancers. In contrast, ER(-) cancers display a significantly lower MDI, revealing a striking epigenomic distinction between cancer hormone receptor subtypes. Kaplan-Meier survival curves of MDI-based risk classes showed significant divergence between low- and high-risk groups. MDI showed superior prognostic performance to crude methylation levels, and MDI retained prognostic significance (P < 0.01) in Cox multivariate analysis, including clinical stage and pathological grade. Most MDI targets individually are significant markers of ER(+) cancer survival. Lymphoid and mesenchymal indexes were not substantially different between ER(+) and ER(-) groups and do not explain MDI dichotomy. However, the mesenchymal index was associated with ER(+) cancer survival, and a high lymphoid index was associated with medullary carcinoma. Finally, a comparison between metastases and primary tumors suggests methylation patterns are established early and maintained through disease progression for both ER(+) and ER(-) tumors.
authors.affiliation: Genetics Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.forename: Sven
authors.initials: S
authors.lastname: Bilke
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.forename: Erich
authors.initials: E
authors.lastname: Jaeger
authors.forename: M Scott
authors.initials: MS
authors.lastname: Killian
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Waterfall
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: William I
authors.initials: WI
authors.lastname: Smith
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D008137:Longitudinal Studies; D008214:Lymphocytes / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen