Integrative molecular concept modeling of prostate cancer progression

Scott A. Tomlins, Rohit Mehra, Daniel R. Rhodes, Xuhong Cao, Lei Wang, Saravana M. Dhanasekaran, Shanker Kalyana-Sundaram, John T. Wei, Mark A. Rubin, Kenneth J. Pienta, Rajal B. Shah, Arul M. Chinnaiyan

Research output: Contribution to journalArticle

659 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)41-51
Number of pages11
JournalNature genetics
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Tomlins, S. A., Mehra, R., Rhodes, D. R., Cao, X., Wang, L., Dhanasekaran, S. M., Kalyana-Sundaram, S., Wei, J. T., Rubin, M. A., Pienta, K. J., Shah, R. B., & Chinnaiyan, A. M. (2007). Integrative molecular concept modeling of prostate cancer progression. Nature genetics, 39(1), 41-51. https://doi.org/10.1038/ng1935