Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

Abstract

Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

The epigenetic landscape of renal cancer

“…In the past 15 years, most research has focused on identifying changes in the methylation patterns of CpG-rich islands near or in gene promoters, which are clearly directly linked to gene silencing 48,49 . Nevertheless, many other genomic regions also have differential (tissue-specific), or aberrant (cancer) CpG methylation patterns [50][51][52][53][54] . Here, we will discuss the well-defined relationship between tumour specific CpG island methylation and gene silencing.…”

Risk Factors contributing to Methylation Shifts in BRCA1 and associated genes in African Americans with Triple Negative Breast Cancer

“…Although BRCA1 mutations only account for 10-20% of all TNBCs, they do show strikingly similar pathological features to breast cancer caused by germ-line BRCA1 mutations. What can be deduced from this is that BRCA1 promoter region is being inactivated through epigenetic hypermethylation [37,38,10]. One study emphasized the important role hypermethylation played versus mutation where they compared TNBC to non-TNBC cases.…”

“…They also observed methylation patterns in the Wilms Tumor (WT1) gene, where if the gene body is methylated the prognosis is poor. But if the promoter region is methylated the prognosis improves, providing vital information for stratifying prognostic outcome in TNBC [37]. What should also be discussed are the risks that influence changes in methylation frequency to stay ahead of the cancer risk.…”

Genome-wide DNA methylation profiling in triple-negative breast cancer reveals epigenetic signatures with important clinical value

“…In our recently published study, 6 we were motivated to specifically investigate the DNA methylome of TNBC to identify epigenetic changes unique to TNBC and any association with disease outcome. To this end, we performed whole-genome methyl-CpG binding domain (MBD)-based capture sequencing (MBDCap-seq) on formalin-fixed paraffin-embedded (FFPE) triple-negative clinical tumors and matched normal DNA samples with known clinical outcome data.…”

“…The potential use of DNA methylation signatures as biomarkers of disease is now being assessed, with a number of studies documenting aberrant methylation events in breast carcinogenesis, as well as identifying specific DNA methylation biomarkers that have significant diagnostic and prognostic potential. 6 To date, several studies have described DNA methylation signatures that can distinguish between ER-positive and ERnegative tumors, and some of these are also predictive of outcome, but no study to date has focused on TNBC methylation.…”