Researchers in the US have discovered that the male hormone androgen may trigger the gene fusion that leads to the development of prostate cancer: they found that pieces of chromosome that normally sit far apart, relocate near each other after exposure to androgen, and this sets the scene for the genes to fuse.

The study, which was funded by the National Institutes of Health (an agency of the US Department of Defense), was the work of researchers at the University of Michigan (U-M) Medical School, Ann Arbor, and was published early online in Science Express.

Scientists already know that gene fusions play a crucial role in the development of cancer, but the underlying mechanisms are poorly understood.

Before this latest work, with his colleagues in 2005, co-author Dr Chinnaiyan, who is director of the Michigan Center for Translational Pathology and SP Hicks Professor of Pathology at the U-M Medical School, found that 50 per cent of human prostate cancers involve the fusion of a region of the androgen-regulated gene TMPRSS2 and the protein-coding sequences of ERG, which encodes an ETS transcription factor. This fusion was essentially an “on switch” for triggering prostate cancer.

Now, with this latest work, Chinnaiyan, who is also a Howard Hughes Medical Institute investigator, told media that they uncovered:

“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,” he added.

For the study, the researchers took prostate cancer cells that did not show signs of the two genes having fused, but were sensitive to androgen, a male hormone that is known to play a role in the development of prostate cancer.

First they exposed the prostate cancer cells to androgen and discovered that two pieces of chromosome that normally reside far apart moved to positions near each other.

Then they exposed the androgen-stimulated cells to gamma radiation, to stress the cells and cause breaks in their DNA strands. They found this caused the TMPRSS2 and ERG genes to fuse.

They concluded that:

“These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling”.

Lead author Dr Ram-Shankar Mani, a research fellow in pathology at the U-M Medical School, said they had originally thought the gene fusion was a chance event, but now they have discovered this is not the case.

“Chromosomes can actually be induced in three-dimensional space to be close to each other,” he said, “then when an insult to the DNA occurs, the fusion happens.”

The researchers think the study may help to understand what lies behind gene fusions in other cancers, and thus lead to new screening tools and even perhaps ways to prevent cancers from developing.

The American Cancer Society estimates that in 2009 over 192,000 Americans will be diagnosed with prostate cancer and over 27,000 will die from it.

The University of Michigan has filed for a patent on prostate cancer gene fusion detection. Chinnaiyan, who is listed as the patent co-inventor, along with another study author, has a sponsored research agreement with Gen-Probe Inc. According to the media statement issued by the university, Gen-Probe did not take part in the design or implementation of the study and was not involved in writing it up.

“Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer.”
Ram-Shankar Mani, Scott A. Tomlins, Kaitlin Callahan, Aparna Ghosh, Mukesh K. Nyati, Sooryanarayana Varambally, Nallasivam Palanisamy, Arul M. Chinnaiyan.
Science, Published Online October 29, 2009.
DOI: 10.1126/science.1178124

Additional sources: University of Michigan Health System.

Written by: Catharine Paddock, PhD