Background: Gene expression signatures have been commonly used as diagnostic and prognostic markers for cancer subtyping. However, expression signatures frequently include many passengers, which are not directly related to cancer progression. Their upstream regulators such as transcription factors (TFs) may take a more critical role as drivers or master regulators to provide better clues on the underlying regulatory mechanisms and therapeutic applications.Results: In order to identify prognostic master regulators, we took the known 85 prognostic signature genes for colorectal cancer and inferred their upstream TFs. To this end, a global transcriptional regulatory network was constructed with total >200,000 TF-target links using the ARACNE algorithm. We selected the top 10 TFs as candidate master regulators to show the highest coverage of the signature genes among the total 846 TF-target sub-networks or regulons. The selected TFs showed a comparable or slightly better prognostic performance than the original 85 signature genes in spite of greatly reduced number of marker genes from 85 to 10. Notably, these TFs were selected solely from inferred regulatory links using gene expression profiles and included many TFs regulating tumorigenic processes such as proliferation, metastasis, and differentiation.Conclusions: Our network approach leads to the identification of the upstream transcription factors for prognostic signature genes to provide leads to their regulatory mechanisms. We demonstrate that our approach could identify upstream biomarkers for a given set of signature genes with markedly smaller size and comparable performances. The utility of our method may be expandable to other types of signatures such as diagnosis and drug response.
Bibliographical noteFunding Information:
SK was supported by the grants of the Global Frontier (2010–0029785) and the Research Information Center Supporting Program (2012–0000350) and the WCU project (R31-2008-000-10103-0) of the Ministry of Science, ICT and Future Planning, and Korea Healthcare Technology (A092255-0911-1110100) of the Ministry of Health and Welfare Affairs of Korean Government, and supported by a grant from Gyeonggi Research Development Program. WK was supported by the grants of National Research Foundation (No 2011– 014992; 2012M3A9C5048707; 2012M3A9D1054744) of the Ministry of Science, ICT and Future Planning of Korean Government.
All Science Journal Classification (ASJC) codes
- Structural Biology
- Modelling and Simulation
- Molecular Biology
- Computer Science Applications
- Applied Mathematics