Submitted on June 23, 2009
Accepted on October 21, 2009
Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer
Ram-Shankar Mani 1, Scott A. Tomlins 1, Kaitlin Callahan 1, Aparna Ghosh 1, Mukesh K. Nyati 2, Sooryanarayana Varambally 3, Nallasivam Palanisamy 4, Arul M. Chinnaiyan 5*
1 Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2 Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3 Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4 Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5 Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
* To whom correspondence should be addressed.
Arul M. Chinnaiyan , E-mail: arul{at}umich.edu
Gene fusions play a critical role in cancer progression. The mechanisms underlying their genesis and cell type specificity are not well understood. About 50% of human prostate cancers display a gene fusion involving the 5’untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an ETS transcription factor. Studying human prostate cancer cells by fluorescence in situ hybridization, we show that androgen signaling induces proximity of the TMPRSS2 and ERG genomic loci, both located on chromosome 21q22.2. Subsequent exposure of the cells to gamma-irradiation, which causes DNA double strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling.
