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. 2016 Sep 27:6:33435.
doi: 10.1038/srep33435.

DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients

Andrea Mathe  1   2 , Michelle Wong-Brown  1   2 , Warwick J Locke  3   4 , Clare Stirzaker  3   4 , Stephen G Braye  5 , John F Forbes  2   6 , Susan J Clark  3   4 , Kelly A Avery-Kiejda  1   2 , Rodney J Scott  1   2   5
Affiliations

DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients

Andrea Mathe et al. Sci Rep. .

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Our previous study identified 38 TNBC-specific genes with altered expression comparing tumour to normal samples. This study aimed to establish whether DNA methylation contributed to these expression changes in the same cohort as well as disease progression from primary breast tumour to lymph node metastasis associated with changes in the epigenome. We obtained DNA from 23 primary TNBC samples, 12 matched lymph node metastases, and 11 matched normal adjacent tissues and assayed for differential methylation profiles using Illumina HumanMethylation450 BeadChips. The results were validated in an independent cohort of 70 primary TNBC samples. The expression of 16/38 TNBC-specific genes was associated with alteration in DNA methylation. Novel methylation changes between primary tumours and lymph node metastases, as well as those associated with survival were identified. Altered methylation of 18 genes associated with lymph node metastasis were identified and validated. This study reveals the important role DNA methylation plays in altered gene expression of TNBC-specific genes and lymph node metastases. The novel insights into progression of TNBC to secondary disease may provide potential prognostic indicators for this hard-to-treat breast cancer subtype.

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Figures

Figure 1
Figure 1. Summary of the DNA methylation comparing primary tumours (IDC) versus matched normal adjacent tissue (NAT) in the study cohort (blue) and the validation cohort (orange).
The top two Venn diagrams show hyper- and hypomethylation of single loci, and the bottom two Venn diagrams show hyper- and hypomethylation of differentially methylated regions (DMRs). The number of validated methylation probes is shown in the middle of each Venn diagram. Underneath the validated number of probes, the number of these probes that are located within promoter and enhancer regions is shown (top two Venn diagrams).
Figure 2
Figure 2. Survival analysis of the EGR1 probe cg07336840.
The y-axis shows the percent of survival of patients within the validation cohort. The x-axis shows the number of months of survival since diagnosis. The blue line represents patients with low DNA methylation of this probe, whereas the red line represents patients with high DNA methylation of this probe.
Figure 3
Figure 3. Unsupervised Hierarchical clustering of the DNA methylation of the significant 16/38 TNBC specific genes.
Primary tumour TNBC (IDC) samples are shown in red and matched normal adjacent tissue (NAT) samples are shown in blue in the sample tree on the left (y-axis). Genes are clustered along the x-axis. Hypomethylation is shown in blue, hypermethylation is shown in red and equivocal methylation is shown in grey.
Figure 4
Figure 4. Survival analysis of nine probes that show significant methylation changes comparing lymph node metastasis to matched normal adjacent tissue.
The x-axis shows the number of months of survival since diagnosis. The green line represents patients with low DNA methylation of this probe, whereas the red line represents patients with high DNA methylation of this probe.
See this image and copyright information in PMC

References

    1. Carotenuto P. et al. Triple negative breast cancer: from molecular portrait to therapeutic intervention. Crit Rev Eukaryot Gene Expr 20, 17–34 (2010). - PubMed
    1. Chacon R. D. & Costanzo M. V. Triple-negative breast cancer. Breast Cancer Res 12 Suppl 2, S3 (2010). - PMC - PubMed
    1. Chen J. Q. & Russo J. E. Ralpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim Biophys Acta 1796, 162–175 (2009). - PMC - PubMed
    1. Wong-Brown M. W. et al. Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat 150, 71–80 (2015). - PubMed
    1. Szasz A. M. et al. The CIN4 chromosomal instability qPCR classifier defines tumor aneuploidy and stratifies outcome in grade 2 breast cancer. PLos One 8, e56707 (2013). - PMC - PubMed