A Methyl-Deviator Epigenotype of Estrogen Receptor-Positive Breast Carcinoma Is Associated with Malignant Biology

作者：Killian J Keith; Bilke Sven; Davis Sean; Walker Robert L; Jaeger Erich; Killian M Scott; Waterfall Joshua J; Bibikova Marina; Fan Jian Bing; Smith William I Jr; Meltzer Paul S^*

来源：American Journal Of Pathology, 2011, 179(1): 55-65.

DOI：10.1016/j.ajpath.2011.03.022

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. (Am J Pathol 2011, 179:55-65; DOI: 10.1016/j.ajpath.2011.03.022)

• 出版日期2011-7