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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.


Ten TFs as potential master drivers of DNA repair dysregulation in breast cancer.TFs selected by the LASSO-based statistical framework were sorted by the number of their predicted DNA repair targets; only the top ten TFs and their targets are shown. The target repair genes are grouped according to pathway participation. Node size indicates level of differential expression.
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f3: Ten TFs as potential master drivers of DNA repair dysregulation in breast cancer.TFs selected by the LASSO-based statistical framework were sorted by the number of their predicted DNA repair targets; only the top ten TFs and their targets are shown. The target repair genes are grouped according to pathway participation. Node size indicates level of differential expression.

Mentions: Among the TFs identified by the LASSO-based statistical framework, some are predicted to target multiple genes within the same repair pathway, and therefore may be particularly important for the dysregulation of that pathway. Moreover, these TFs may also target genes that function in different repair pathways, and hence may be able to exert a global influence on the dysregulation of several repair pathways. With these thoughts in mind, we sorted the identified TFs according to the number of genes that they target. The top ten TFs and their pathway-specific targets are shown in Fig. 3. We consider these TFs as potential master drivers of DNA repair dysregulation in breast cancer.


Integrating Multi-omics Data to Dissect Mechanisms of DNA repair Dysregulation in Breast Cancer
Ten TFs as potential master drivers of DNA repair dysregulation in breast cancer.TFs selected by the LASSO-based statistical framework were sorted by the number of their predicted DNA repair targets; only the top ten TFs and their targets are shown. The target repair genes are grouped according to pathway participation. Node size indicates level of differential expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Ten TFs as potential master drivers of DNA repair dysregulation in breast cancer.TFs selected by the LASSO-based statistical framework were sorted by the number of their predicted DNA repair targets; only the top ten TFs and their targets are shown. The target repair genes are grouped according to pathway participation. Node size indicates level of differential expression.
Mentions: Among the TFs identified by the LASSO-based statistical framework, some are predicted to target multiple genes within the same repair pathway, and therefore may be particularly important for the dysregulation of that pathway. Moreover, these TFs may also target genes that function in different repair pathways, and hence may be able to exert a global influence on the dysregulation of several repair pathways. With these thoughts in mind, we sorted the identified TFs according to the number of genes that they target. The top ten TFs and their pathway-specific targets are shown in Fig. 3. We consider these TFs as potential master drivers 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.