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Integrating Multi-omics Data to Dissect Mechanisms of DNA repair Dysregulation in Breast Cancer

View Article: PubMed Central - PubMed

ABSTRACT

DNA repair genes and pathways that are transcriptionally dysregulated in cancer provide the first line of evidence for the altered DNA repair status in tumours, and hence have been explored intensively as a source for biomarker discovery. The molecular mechanisms underlying DNA repair dysregulation, however, have not been systematically investigated in any cancer type. In this study, we performed a statistical analysis to dissect the roles of DNA copy number alteration (CNA), DNA methylation (DM) at gene promoter regions and the expression changes of transcription factors (TFs) in the differential expression of individual DNA repair genes in normal versus tumour breast samples. These gene-level results were summarised at pathway level to assess whether different DNA repair pathways are affected in distinct manners. Our results suggest that CNA and expression changes of TFs are major causes of DNA repair dysregulation in breast cancer, and that a subset of the identified TFs may exert global impacts on the dysregulation of multiple repair pathways. Our work hence provides novel insights into DNA repair dysregulation in breast cancer. These insights improve our understanding of the molecular basis of the DNA repair biomarkers identified thus far, and have potential to inform future biomarker discovery.

No MeSH data available.


The effects of DM on DNA repair gene expression.Distributions of the in cis Spearman correlations between DM and mRNA expression, summarised for all differentially expressed DNA repair genes, or only genes from each repair pathway.
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f2: The effects of DM on DNA repair gene expression.Distributions of the in cis Spearman correlations between DM and mRNA expression, summarised for all differentially expressed DNA repair genes, or only genes from each repair pathway.

Mentions: To evaluate the effects of CNA and DM on DNA repair dysregulation, for each of the differentially expressed repair genes (Table 1), we measured the respective correlations of mRNA with CNA (Fig. 1 and Table 2) and DM (Fig. 2 and Table 3) using Spearman correlation coefficients.


Integrating Multi-omics Data to Dissect Mechanisms of DNA repair Dysregulation in Breast Cancer
The effects of DM on DNA repair gene expression.Distributions of the in cis Spearman correlations between DM and mRNA expression, summarised for all differentially expressed DNA repair genes, or only genes from each repair pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036051&req=5

f2: The effects of DM on DNA repair gene expression.Distributions of the in cis Spearman correlations between DM and mRNA expression, summarised for all differentially expressed DNA repair genes, or only genes from each repair pathway.
Mentions: To evaluate the effects of CNA and DM on DNA repair dysregulation, for each of the differentially expressed repair genes (Table 1), we measured the respective correlations of mRNA with CNA (Fig. 1 and Table 2) and DM (Fig. 2 and Table 3) using Spearman correlation coefficients.

View Article: PubMed Central - PubMed

ABSTRACT

DNA repair genes and pathways that are transcriptionally dysregulated in cancer provide the first line of evidence for the altered DNA repair status in tumours, and hence have been explored intensively as a source for biomarker discovery. The molecular mechanisms underlying DNA repair dysregulation, however, have not been systematically investigated in any cancer type. In this study, we performed a statistical analysis to dissect the roles of DNA copy number alteration (CNA), DNA methylation (DM) at gene promoter regions and the expression changes of transcription factors (TFs) in the differential expression of individual DNA repair genes in normal versus tumour breast samples. These gene-level results were summarised at pathway level to assess whether different DNA repair pathways are affected in distinct manners. Our results suggest that CNA and expression changes of TFs are major causes of DNA repair dysregulation in breast cancer, and that a subset of the identified TFs may exert global impacts on the dysregulation of multiple repair pathways. Our work hence provides novel insights into DNA repair dysregulation in breast cancer. These insights improve our understanding of the molecular basis of the DNA repair biomarkers identified thus far, and have potential to inform future biomarker discovery.

No MeSH data available.