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Integrative molecular concept modeling of prostate cancer progression

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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References

  1. Jemal, A. et al. Cancer statistics, 2005. CA Cancer J. Clin. 55, 10–30 (2005).

    Article  PubMed  Google Scholar 

  2. Nelson, P.S. Predicting prostate cancer behavior using transcript profiles. J. Urol. 172, S28–S32 (2004).

    CAS  PubMed  Google Scholar 

  3. Ashida, S. et al. Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Cancer Res. 64, 5963–5972 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Bostwick, D.G. & Qian, J. High-grade prostatic intraepithelial neoplasia. Mod. Pathol. 17, 360–379 (2004).

    Article  PubMed  Google Scholar 

  5. De Marzo, A.M., Marchi, V.L., Epstein, J.I. & Nelson, W.G. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am. J. Pathol. 155, 1985–1992 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. DeMarzo, A.M., Nelson, W.G., Isaacs, W.B. & Epstein, J.I. Pathological and molecular aspects of prostate cancer. Lancet 361, 955–964 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Gleason, D.F. & Mellinger, G.T. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J. Urol. 111, 58–64 (1974).

    Article  CAS  PubMed  Google Scholar 

  8. Humphrey, P.A. Gleason grading and prognostic factors in carcinoma of the prostate. Mod. Pathol. 17, 292–306 (2004).

    Article  PubMed  Google Scholar 

  9. True, L. et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc. Natl. Acad. Sci. USA 103, 10991–10996 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Best, C.J. et al. Molecular differentiation of high- and moderate-grade human prostate cancer by cDNA microarray analysis. Diagn. Mol. Pathol. 12, 63–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl. Acad. Sci. USA 101, 811–816 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Singh, D. et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1, 203–209 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Welsh, J.B. et al. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res. 61, 5974–5978 (2001).

    CAS  PubMed  Google Scholar 

  14. Vanaja, D.K., Cheville, J.C., Iturria, S.J. & Young, C.Y. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63, 3877–3882 (2003).

    CAS  PubMed  Google Scholar 

  15. Mootha, V.K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Segal, E., Friedman, N., Koller, D. & Regev, A. A module map showing conditional activity of expression modules in cancer. Nat. Genet. 36, 1090–1098 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rhodes, D.R. & Chinnaiyan, A.M. Integrative analysis of the cancer transcriptome. Nat. Genet. 37 (Suppl.), S31–S37 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Rhodes, D.R. et al. Mining for regulatory programs in the cancer transcriptome. Nat. Genet. 37, 579–583 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Tomlins, S.A. et al. Whole transcriptome amplification for gene expression profiling and development of molecular archives. Neoplasia 8, 153–162 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rhodes, D.R. et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1–6 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Varambally, S. et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 8, 393–406 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Quinn, D.I., Henshall, S.M. & Sutherland, R.L. Molecular markers of prostate cancer outcome. Eur. J. Cancer 41, 858–887 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Sato, K. et al. Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. J. Natl. Cancer Inst. 91, 1574–1580 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Kristiansen, G. et al. Expression profiling of microdissected matched prostate cancer samples reveals CD166/MEMD and CD24 as new prognostic markers for patient survival. J. Pathol. 205, 359–376 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Moore, S. et al. Loss of stearoyl-CoA desaturase expression is a frequent event in prostate carcinoma. Int. J. Cancer 114, 563–571 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Stuart, R.O. et al. In silico dissection of cell-type-associated patterns of gene expression in prostate cancer. Proc. Natl. Acad. Sci. USA 101, 615–620 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sumitomo, M. et al. Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN. Cancer Cell 5, 67–78 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Dhanasekaran, S.M. et al. Delineation of prognostic biomarkers in prostate cancer. Nature 412, 822–826 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Koyabu, Y., Nakata, K., Mizugishi, K., Aruga, J. & Mikoshiba, K. Physical and functional interactions between Zic and Gli proteins. J. Biol. Chem. 276, 6889–6892 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Paris, P.L. et al. Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors. Hum. Mol. Genet. 13, 1303–1313 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Nupponen, N.N., Kakkola, L., Koivisto, P. & Visakorpi, T. Genetic alterations in hormone-refractory recurrent prostate carcinomas. Am. J. Pathol. 153, 141–148 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Tomlins, S.A. et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 66, 3396–3400 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Glinsky, G.V., Glinskii, A.B., Stephenson, A.J., Hoffman, R.M. & Gerald, W.L. Gene expression profiling predicts clinical outcome of prostate cancer. J. Clin. Invest. 113, 913–923 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Konishi, N., Shimada, K., Ishida, E. & Nakamura, M. Molecular pathology of prostate cancer. Pathol. Int. 55, 531–539 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Trotman, L.C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tran, H., Brunet, A., Griffith, E.C. & Greenberg, M.E. The many forks in FOXO's road. Sci. STKE 2003, RE5 (2003).

    Article  PubMed  Google Scholar 

  39. Vailancourt, L. et al. Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study. Am. J. Surg. Pathol. 20, 86–93 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Tomlins, S.A., Rubin, M.A. & Chinnaiyan, A.M. Integrative biology of prostate cancer progression. Ann. Rev. Pathol. Mech. Dis. 1, 243–271 (2006).

    Article  CAS  Google Scholar 

  41. De Marzo, A.M. et al. Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment. J. Cell. Biochem. 91, 459–477 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Fischer, A.H., Bardarov, S., Jr. & Jiang, Z. Molecular aspects of diagnostic nucleolar and nuclear envelope changes in prostate cancer. J. Cell. Biochem. 91, 170–184 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Ruggero, D. & Pandolfi, P.P. Does the ribosome translate cancer? Nat. Rev. Cancer 3, 179–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Hendriksen, P.J. et al. Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res. 66, 5012–5020 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Stanbrough, M. et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66, 2815–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Chen, C.D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004).

    Article  PubMed  CAS  Google Scholar 

  47. Feldman, B.J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Lin, B. et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 59, 4180–4184 (1999).

    CAS  PubMed  Google Scholar 

  49. Rhodes, D.R. et al. Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc. Natl. Acad. Sci. USA 101, 9309–9314 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Storey, J.D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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

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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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