Abstract P3-04-01: Integrated Analysis of Epigenetic Signatures Associated with Inflammatory Breast Cancer

Abstract

Abstract Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary epithelial breast cancer and differs from non-IBC both from a clinical and a biological perspective. The high metastatic potential of IBC is highlighted by the low 5-year survival rate of 50%. The biological features that make IBC unique are its rapid local growth, its high angioinvasive capability with early metastasis and its aggressive behavior from inception. These differences could be the result of key changes in the epigenetic profile of IBC. To address this issue, we compared the levels of epigenetic regulation in IBC (N=19) and non-IBC (N=43) samples at the methylome (DNA methylation), miRome (miRNA) and transcriptome (mRNA) level using high-throughput molecular technologies. Differences in gene expression profiles allowed the classification of samples according to tumor subtype (IBC vs non-IBC). The analysis of 27,578 CpG loci demonstrated that the largest variation in methylation levels between samples was attributable to differences in metastatic status (P=0.026) and patients’ age (P=0.049). About 2% of all interrogated CpG loci was differentially methylated in IBC and non-IBC (FDR <0.1). Annotated gene functions for these CpG loci were enriched for biological processes related to inflammation and immune response. Using a whole genome approach, we observed significant, negative correlations between methylation and mRNA levels for 38% of genes. For 8% of genes, a significant, positive correlation was observed. Interrogated CpG loci for these genes were more frequently located in the gene body (>500 bp from TSS) (P=0.008). Our analysis of 322 miRNAs showed that the largest variation in miRNA levels between samples was attributable to differences in ER status (P=0.001) and histological grade (P=0.002). About 4% of all miRNAs was expressed at different levels in IBC and non-IBC. Using a whole genome approach, we identified 17,295 of highly correlated miRNA-mRNA pairs for these IBC-associated miRNAs. Based on this miRNA target gene information, we were able to detect a variety of biological processes that may indicate function of these miRNAs and to indicate potential associations of these miRNAs with prognosis in breast cancer. Furthermore, the comparison of mRNA levels of key miRNA processing genes revealed the upregulation of Ago2 (P=0.002) and the downregulation of Dicer (P=0.004) in IBC when compared to non-IBC, which may suggest higher RISC activities and, therefore, that miRNAs regulate target gene expression in IBC with higher efficiency. In conclusion, this study represents the first integrated analysis of epigenetic signatures in IBC. Using high-throughput technologies, we were able to identify a number of epigenetic markers specifically associated with IBC. A global initiative has been taken to set up an IBC tissue repository that will allow the confirmation of these kinds of studies on a larger IBC sample population. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-01.