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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


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.
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f2: 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.

Mentions: We have previously identified 66 genes to be differentially expressed in primary tumour samples compared to normal adjacent tissue in TNBC16. Therefore, in this study we aimed to identify the contribution of DNA methylation aberration to these gene expression changes. We determined that 26 of the 66 genes had significantly altered methylation of single loci (a total of 63 probes, 47.6% hypomethylated, 52.4% hypermethylated) in both the study and the validation cohorts (Supplementary Table 3). Of the significant probes there were nine within enhancers and four within promoter regions. Additionally, eight of the 66 genes had significantly altered regional methylation (40 probes, 30% hypomethylated, 70% hypermethylated) in both cohorts (Table 1). Of the eight genes with significantly altered regional methylation, one of these (EGR1) was significantly associated with overall survival in one probe (cg07336840). High DNA methylation of this probe was associated with better survival as shown in Fig. 2.


DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients
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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037364&req=5

f2: 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.
Mentions: We have previously identified 66 genes to be differentially expressed in primary tumour samples compared to normal adjacent tissue in TNBC16. Therefore, in this study we aimed to identify the contribution of DNA methylation aberration to these gene expression changes. We determined that 26 of the 66 genes had significantly altered methylation of single loci (a total of 63 probes, 47.6% hypomethylated, 52.4% hypermethylated) in both the study and the validation cohorts (Supplementary Table 3). Of the significant probes there were nine within enhancers and four within promoter regions. Additionally, eight of the 66 genes had significantly altered regional methylation (40 probes, 30% hypomethylated, 70% hypermethylated) in both cohorts (Table 1). Of the eight genes with significantly altered regional methylation, one of these (EGR1) was significantly associated with overall survival in one probe (cg07336840). High DNA methylation of this probe was associated with better survival as shown in Fig. 2.

View Article: PubMed Central - PubMed

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.

No MeSH data available.