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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.

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Related in: MedlinePlus

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.
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f4: 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.

Mentions: It was not possible to validate the methylation changes in the validation cohort due to the lack of LN samples. However, we hypothesised that due to their altered expression in LN metastases, they would be associated with survival outcome. We performed survival analysis on the 70 tumour samples from our validation cohort using the methylation analysis of the 74 probes that comprised the 14 DMRs. Nine of the 74 probes were significantly associated with survival in the TNBC validation cohort (cg18108818, cg20464151, cg09933058, cg24173596, cg07336840, cg08500417, cg20066782, cg04028606, cg00185066) (Fig. 4). Eight of these probes (cg18108818, cg20464151, cg24173596, cg07336840, cg08500417, cg20066782, cg04028606, cg00185066) were associated with improved survival when they were highly methylated and one probe (cg09933058) was associated with worse survival when it was highly methylated.


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

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

f4: 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.
Mentions: It was not possible to validate the methylation changes in the validation cohort due to the lack of LN samples. However, we hypothesised that due to their altered expression in LN metastases, they would be associated with survival outcome. We performed survival analysis on the 70 tumour samples from our validation cohort using the methylation analysis of the 74 probes that comprised the 14 DMRs. Nine of the 74 probes were significantly associated with survival in the TNBC validation cohort (cg18108818, cg20464151, cg09933058, cg24173596, cg07336840, cg08500417, cg20066782, cg04028606, cg00185066) (Fig. 4). Eight of these probes (cg18108818, cg20464151, cg24173596, cg07336840, cg08500417, cg20066782, cg04028606, cg00185066) were associated with improved survival when they were highly methylated and one probe (cg09933058) was associated with worse survival when it was highly methylated.

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.


Related in: MedlinePlus