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Integrative molecular concept modeling of prostate cancer progression

Nature Genetics volume 39, pages 41–51 (2007)Cite this article

Abstract

Despite efforts to profile prostate cancer, the genetic alterations and biological processes that correlate with the observed histological progression are unclear. Using laser-capture microdissection to isolate 101 cell populations, we have profiled prostate cancer progression from benign epithelium to metastatic disease. By analyzing expression signatures in the context of over 14,000 'molecular concepts', or sets of biologically connected genes, we generated an integrative model of progression. Molecular concepts that demarcate critical transitions in progression include protein biosynthesis, E26 transformation-specific (ETS) family transcriptional targets, androgen signaling and cell proliferation. Of note, relative to low-grade prostate cancer (Gleason pattern 3), high-grade cancer (Gleason pattern 4) shows an attenuated androgen signaling signature, similar to metastatic prostate cancer, which may reflect dedifferentiation and explain the clinical association of grade with prognosis. Taken together, these data show that analyzing gene expression signatures in the context of a compendium of molecular concepts is useful in understanding cancer biology.

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Figure 1: Integrative analysis of molecular concepts in prostate cancer progression.
Figure 2: Expression signatures and molecular concept analysis of cancer progression in microdissected prostatic epithelia.
Figure 3: Molecular concept analysis comparing benign epithelium with prostatic intraepithelial neoplasia (PIN).
Figure 4: Prostate cancers with and without ETS family overexpression have distinct expression signatures involving chromosome 6q21.
Figure 5: Differential expression of proliferation, protein biosynthesis and androgen signaling concepts in clinically localized, hormone-naive metastatic and hormone-refractory metastatic prostate cancer.
Figure 6: Molecular concept analysis comparing low–Gleason grade to high–Gleason grade prostate cancer.
Figure 7: Molecular concept heat map of prostate cancer progression.
Figure 8: Molecular concept model of prostate cancer progression.

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Acknowledgements

We thank A. Menon for microarray production, B. Briggs, S. Varambally and B. Helgeson for technical assistance and R. Kuefer (University of Ulm) for tissue samples. Supported in part by Department of Defense (grants DAMD17-03-2-0033 to A.M.C. and M.A.R., PC040517 to R.M. and W81XWH-06-1-0224 to A.M.C.), the US National Institutes of Health (U54 DA021519-01A1 to A.M.C., R01 CA102872 to K.J.P and A.M.C and Prostate SPORE P50CA69568 to K.J.P., A.M.C. and R.B.S.), the Early Detection Research Network (UO1 CA111275-01 to A.M.C.) and the Cancer Center Bioinformatics Core (support grant 5P30 CA46592). K.J.P. is supported as an American Cancer Society Clinical Research Professor, D.R.R. is supported by the Cancer Biology Training Program, S.A.T. is supported by a Rackham Predoctoral Fellowship, A.M.C. is supported by a Clinical Translational Research Award from the Burroughs Welcome Foundation and S.A.T. and D.R.R. are Fellows of the Medical Scientist Training Program.

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Author notes

  1. Scott A Tomlins, Rohit Mehra and Daniel R Rhodes: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Scott A Tomlins, Rohit Mehra, Daniel R Rhodes, Xuhong Cao, Lei Wang, Saravana M Dhanasekaran, Shanker Kalyana-Sundaram, Rajal B Shah & Arul M Chinnaiyan

  2. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Rohit Mehra, Daniel R Rhodes, John T Wei, Kenneth J Pienta, Rajal B Shah & Arul M Chinnaiyan

  3. Bioinformatics Program, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Daniel R Rhodes & Arul M Chinnaiyan

  4. Department of Urology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    John T Wei, Kenneth J Pienta, Rajal B Shah & Arul M Chinnaiyan

  5. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Mark A Rubin

  6. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Mark A Rubin

  7. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Kenneth J Pienta

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Contributions

R.B.S. and A.M.C. share senior authorship.

Corresponding author

Correspondence to Arul M Chinnaiyan.

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Competing interests

Oncomine and the Molecular Concepts Map (MCM), which are utilized in this manuscript, are freely available to the academic community. The University of Michigan has licensed the commercial rights of Oncomine and MCM to Compendia Biosciences, Inc., which was cofounded by A.M.C. and D.R.R.

Supplementary information

Supplementary Fig. 1

Stromal contamination masks epithelial gene expression across prostate cancer profiling studies. (PDF 2277 kb)

Supplementary Fig. 2

Validation of the prostate cancer progression signature. (PDF 778 kb)

Supplementary Fig. 3

Distinct expression patterns between the putative precursor lesions prostatic intraepithelial neoplasia and atrophic epithelium. (PDF 1766 kb)

Supplementary Fig. 4

Marked overexpression of ETS family members through TMPRSS2:ETS gene fusions characterize the transition from prostatic intraepithelial neoplasia to prostate cancer in a majority of cases. (PDF 687 kb)

Supplementary Fig. 5

Molecular concepts analysis comparing clinically localized prostate cancer to hormone refractory metastatic prostate cancer. (PDF 967 kb)

Supplementary Table 1

Oligonucleotide primers. (PDF 70 kb)

Supplementary Discussion (PDF 166 kb)

Supplementary Methods (PDF 259 kb)

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Tomlins, S., Mehra, R., Rhodes, D. et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet 39, 41–51 (2007). https://doi.org/10.1038/ng1935

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