Article abstract
Nature Genetics 39, 41 - 51 (2006)
Published online: 17 December 2006 | doi:10.1038/ng1935
Integrative molecular concept modeling of prostate cancer progression
Scott A Tomlins1,8, Rohit Mehra1,2,8, Daniel R Rhodes1,2,3,8, Xuhong Cao1, Lei Wang1, Saravana M Dhanasekaran1, Shanker Kalyana-Sundaram1, John T Wei2,4, Mark A Rubin5,6, Kenneth J Pienta2,4,7, Rajal B Shah1,2,4 & Arul M Chinnaiyan1,2,3,4
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.
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
- Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
- Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
- Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
- These authors contributed equally to this manuscript.
Correspondence to: Arul M Chinnaiyan1,2,3,4 e-mail: arul@umich.edu
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