Abstract
IntroductionFive different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles.MethodsWe analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay.ResultsUnsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation.ConclusionsWe have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers.
Highlights
Five different molecular subtypes of breast cancer have been identified through gene expression profiling
We found larger fractions altered in tumours in the basal-like-associated Cluster 3 and smaller fractions in tumours of the luminal A (lumA)-associated Cluster 2 (P = 4 × 10-14, analysis of variance (ANOVA); Figure 1c) corroborating earlier findings by Hu et al [32]
Array-based methylation analysis corroborates individual CpG sites associated with clinical parameters To validate the performance of our methylation assay, we investigated the relative methylation levels of genes previously reported as having methylation patterns associated with oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status in breast tumours
Summary
Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Gene silencing and maintenance of cellular identity can be mediated by histone modifications carried out by polycomb group (PcG) proteins. Enhancer of zeste homolog 2 (EZH2) is a core member of the polycomb repressive complex 2 (PRC2) that catalyses the histone mark characteristic for PcG-mediated silencing: trimethylation of lysine 27 on histone H3 (H3K27me3), which leads to the blocking of transcriptional activation factors and thereby gene silencing independent of promoter methylation [5]. The presence of PRC2 can lead to recruitment of DNA methyltransferases (DNMTs) resulting in de novo DNA methylation and more permanent repression of PRC2 target genes [9]. Many of the genes that undergo promoter methylation in cancer are already expressed at low levels in corresponding normal cells, suggesting that a large fraction of de novo methylation events in cancer cells are not subject to growth selection but instead reflect an instructive mechanism inherent of the normal cell from which the tumour originated [10,11]
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