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Mining for regulatory programs in the cancer transcriptome


DNA microarrays have been widely applied to cancer transcriptome analysis. The Oncomine database contains a large collection of such data, as well as hundreds of derived gene-expression signatures. We studied the regulatory mechanisms responsible for gene deregulation in these cancer signatures by searching for the coordinate regulation of genes with common transcription factor binding sites. We found that genes with binding sites for the archetypal cancer transcription factor, E2F, were disproportionately overexpressed in a wide variety of cancers, whereas genes with binding sites for other transcription factors, such as Myc-Max, c-Rel and ATF, were disproportionately overexpressed in specific cancer types. These results suggest that alterations in pathways activating these transcription factors may be responsible for the observed gene deregulation and cancer pathogenesis.

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Figure 1: Overview of the method used to elucidate CRPs.
Figure 2: Regulatory programs encoded in gene-expression signatures.

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We thank D. Gibbs for hardware support and R. Varambally for database support. This research is supported in part by the National Institutes of Health through the University of Michigan's Cancer Center Support Grant, pilot funds from the Dean's Office and the Department of Pathology. D.R.R. was supported by the Medical Scientist Training Program and the Cancer Biology Training Program, and A.M.C. is a Pew Scholar.

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Correspondence to Arul M Chinnaiyan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

CREB1 and ATF5 are over-expressed with the CREB-ATF CRP. (PDF 692 kb)

Supplementary Table 1

Gene expression signatures. (PDF 104 kb)

Supplementary Table 2

Putative regulatory signatures. (PDF 71 kb)

Supplementary Table 3

All conditional regulatory programs — all. (XLS 1187 kb)

Supplementary Table 4

'Normal vs. Normal' conditional regulatory programs. (PDF 69 kb)

Supplementary Table 5

'Cancer vs. Normal' conditional regulatory programs. (PDF 71 kb)

Supplementary Table 6

'Cancer vs. Cancer' conditional regulatory programs. (PDF 72 kb)

Supplementary Table 7

In vitro E2F signature analysis. (PDF 92 kb)

Supplementary Table 8

Transcription factors over-expressed with CRPs. (PDF 80 kb)

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Rhodes, D., Kalyana-Sundaram, S., Mahavisno, V. et al. Mining for regulatory programs in the cancer transcriptome. Nat Genet 37, 579–583 (2005).

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