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A methyl-deviator epigenotype of estrogen receptor-positive breast carcinoma is associated with malignant biology.

Am J Pathol, 2011/7;179(1):55-65.

Killian JK[1], Bilke S, Davis S, Walker RL, Jaeger E, Killian MS, Waterfall JJ, Bibikova M, Fan JB, Smith WI Jr, Meltzer PS

Affiliations

PMID: 21641572DOI: 10.1016/j.ajpath.2011.03.022

Impact factor: 5.77

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.
MeSH terms
Aged; Biomarkers, Tumor; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Carcinoma, Medullary; DNA Methylation; Epigenomics; Female; Gene Expression Regulation, Neoplastic; Humans; Immunophenotyping; Longitudinal Studies; Lymphocytes; Mesoderm; Middle Aged; Neoplasm Invasiveness; Prognosis; Receptors, Estrogen; Survival Rate
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