Study Uncovers Key to How ‘Triggering Event’ in
Prostate Cancer Occurs
Researchers link hormone androgen to creation of gene
fusion in prostate cancer, a major killer of older men; may help learn
how other cancers begin
Arul Chinnaiyan,
M.D., Ph.D., from the University of Michigan Comprehensive
Cancer Center
Oct. 29, 2009 – The switching mechanism that
triggers the start of prostate cancer is the fusion of two genes, a
phenomenon that has been shown to cause prostate cancer to develop,
according to Michigan researchers who have discovered what leads to this
fusion.
The study by researchers at the University of
Michigan Comprehensive Cancer Center found that pieces of chromosome
relocate near each other after exposure to the hormone androgen. This
sets the scene for the gene fusion to occur. The finding is reported
online Oct. 29 in Science Express.
In 2009, 192,280 Americans – primarily senior
citizens - are expected to be diagnosed with prostate cancer and 27,360
will die from the disease, according to the American Cancer Society
MIRP, especially with robotic assistance, increased from 1% to 40% of radical prostatectomies from 2001 to
2006,despite limited data on outcomes and costs
"This work shows the origin of how the gene fusion
is actually created and perhaps the origin of prostate cancer itself.
This is a triggering event for the genesis of prostate cancer," says
study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan
Center for Translational Pathology and S.P. Hicks Professor of Pathology
at the U-M Medical School. Chinnaiyan is also a Howard Hughes Medical
Institute investigator.
Chinnaiyan and his team identified in 2005 a
prostate-specific gene called TMPRSS2 that fuses with the gene ERG,
which is known to play a role in prostate cancer. Their earlier research
has shown that this gene fusion acts as an "on switch" to trigger
prostate cancer. In the current study, the researchers focused on what
causes the gene fusion to occur.
The researchers took prostate cancer cells that did
not reflect the gene fusion but that were sensitive to androgen, a male
hormone known to play a role in some prostate cancers. They exposed the
cells to androgen and found that two pieces of chromosome that are
normally far apart are relocated near each other.
Next, the researchers applied radiation to the
androgen-stimulated cells. This stress or insult to the cells – designed
to induce chromosomal breaks – led to the gene fusion occurring.
"We thought the gene fusions occurred as a chance
event, but it's not. Chromosomes can actually be induced in
three-dimensional space to be close to each other. Then when an insult
to the DNA occurs, the fusion happens," says lead study author
Ram-Shankar Mani, Ph.D., a research fellow in pathology at the U-M
Medical School.
The researchers believe the findings could have
implications for gene fusions that occur in other cancer types. By
understanding how gene fusions occur, the researchers suggest that
screening tools or prevention strategies could potentially be developed.
Additional authors were Scott A. Tomlins, Kaitlin
Callahan, Aparna Ghosh, Mukesh N. Nyati, Sooryanarayana Varambally and
Nallasivam Palanisamy, all from U-M
Funding for the study was by the National
Institutes of Health and the U.S. Department of Defense
Disclosure: The University of Michigan has filed
for a patent on the detection of gene fusions in prostate cancer, on
which Tomlins and Chinnaiyan are co-inventors. The diagnostic field of
use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored
research agreement with Gen-Probe. Gen-Probe has had no role in the
design or experimentation of this study, nor has it participated in the
writing of the manuscript.
Sarcosine is better indicator of advancing disease
than traditional prostate specific antigen test (PSA); it is detected in
urine, researchers hopeful simple urine test can be used
