Studies conducted by various independent groups have confirmed the role of gene fusion, involving TMPRSS2 and ETS genes, in leading to prostate cancer. However, the underlying causative factor for this genetic alteration was poorly understood. Now, results of a recent study published in the journal Science have identified androgen as a triggering factor for inducing gene fusion.
Arul Chinnaiyan, director of the Michigan Center for Translational Pathology, and colleagues from the University of Michigan Medical School, Ann Arbor, USA, performed the study on human prostate cancer cells that did not indicate genetic fusion, but sensitive to androgen. Analysis conducted using fluorescence in situ hybridization demonstrated that the exposure to androgen hormone contributes to the juxtaposition of the TMPRSS2 and ERG genomic loci on chromosome 21q22.2. Exposure of cells to gamma-irradiation, induced the formation of DNA double strand breaks and TMPRSS2-ERG gene fusion. The study results also explain the rationale for the specific occurrence of the gene fusion only in prostate cancer cells: which is its dependence on the signaling of the androgen hormone.
Gene fusion, due to chromosomal rearrangements, has been identified as one of the most prevalent genetic alterations that contribute to the development of neoplasms. However, it was earlier thought to be primarily restricted to hematological malignancies and sarcomas. In 2005, Chinnaiyan and coworkers identified the key role played by TMPRSS2-ERG gene fusion in the development of prostate cancer. The Michigan University scientists, in collaboration with researchers from Brigham and Women’s Hospital and Harvard Medical School, in 2007, confirmed the occurrence of recurrent gene fusions in the 5′ untranslated region of the androgen-regulated gene: TMPRSS2, and the E26 transformation-specific (ETS) family of genes, ETV1, ETV4, or ERG, in most of the prostate neoplasms.
Following this, the university filed a patent application for the discovery of gene fusions in relation to the development of prostate cancer. Additionally, San Diego’s Gen-Probe Incorporated gained the rights to develop diagnostic tests based on this highly specific genetic alteration, which could supplement the currently used prostate-specific antigen (PSA) test. Although PSA has emerged as a standard screening tool for the disease, certain studies have raised concerns regarding the accuracy of the test especially in predicting lethal prostate cancer patients placed under watchful waiting. Since the appropriate clinical adoption of the screening technique is debatable, there is an urgent need for newer diagnostic markers that could effectively distingiush clinically significant prostate cancer subtypes, thereby reducing unwanted biopsies.
Prostate cancer affects 1 in every 6 US men over their life time. According to the National Cancer Institute, the disease is estimated to cause 192,280 new cases and 27,360 deaths in 2009 across the nation.
The novel discovery of androgen’s role in triggering gene fusion holds wider therapeutic implications in light of another recent prospective study suggesting the increased prevalence of TMPRSS2-ERG prostate cancer among North American men undergoing prostate cancer biopsy. Mosquera et al (Clinical Cancer Research, 2009) studied the status of gene rearrangement in 100 cancer and 34 benign biopsies. The researchers noted the rearrangements of ERG in 46% of the biopsies which were diagnosed as cancerous, and 0% in benign samples. These recent findings mark a crucial milestone in the development of efficient screening tools and potential treatment/preventive strategies. However, further analysis of the TMPRSS2-ERG gene fusion mechanism is crucial to better understand the clinical course of prostate cancer.
References
1. U-M study uncovers key to how a triggering event in cancer occurs. Press Release. University of Michigan Health System. Last accessed November 3, 2009.
2. Mani R-S, Tomlins SA, Callahan K, et al. Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer. Science. 2009 October 29. [Epub ahead of print].
3. Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007 Aug 2;448(7153):595-599.
4. Mosquera JM, Mehra R, Regan MM, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 2009 Jul 15;15(14):4706-11.
