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Int J Cancer. 2016 Jan 1;138(1):87-97. doi: 10.1002/ijc.29684. Epub 2015 Jul 30.

Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes.

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MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.
2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.
MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
Oncology Experimental Therapeutics Unit, IRCCS Clinical and Research Institute Humanitas, Rozzano - Milan, Italy.
Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway.
The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.


DNA methylation has a substantial impact on gene expression, affecting the prognosis of breast cancer (BC) patients dependent on molecular subtypes. In this study, we investigated the prognostic relevance of the expression of genes reported as aberrantly methylated, and the link between gene expression and DNA methylation in BC subtypes. The prognostic value of the expression of 144 aberrantly methylated genes was evaluated in ER+/HER2-, HER2+, and ER-/HER2- molecular BC subtypes, in a meta-analysis of two large transcriptomic cohorts of BC patients (n = 1,938 and n = 1,640). The correlation between gene expression and DNA methylation in distinct gene regions was also investigated in an independent dataset of 104 BCs. Survival and Pearson correlation analyses were computed for each gene separately. The expression of 48 genes was significantly associated with BC prognosis (p < 0.05), and 32 of these prognostic genes exhibited a direct expression-methylation correlation. The expression of several immune-related genes, including CD3D and HLA-A, was associated with both relapse-free survival (HR = 0.42, p = 3.5E-06; HR = 0.35, p = 1.7E-08) and overall survival (HR = 0.50, p = 5.5E-04; HR = 0.68, p = 4.5E-02) in ER-/HER2- BCs. On the overall, the distribution of both positive and negative expression-methylation correlation in distinct gene regions have different effects on gene expression and prognosis in BC subtypes. This large-scale meta-analysis allowed the identification of several genes consistently associated with prognosis, whose DNA methylation could represent a promising biomarker for prognostication and clinical stratification of patients with distinct BC subtypes.


DNA methylation biomarkers; breast cancer subtypes; gene expression; immune genes; prognosis

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