Another gene rearrangement involved in prostate cancer identified

Researchers at the University of Michigan Medical School have identified a third gene involved in prostate cancer, expanding their groundbreaking announcement, published last October in Science, that the majority of prostate cancers carry a malignancy-inducing fusion of genes never before seen in solid tumors. The new findings appear in the April 1 issue of Cancer Research. Since prostate cancer is a cancer of the epithelial cells lining organs, lead researcher Arul Chinnaiyan and his colleagues believe it likely that other gene re-arrangements may be responsible for other cancers of epithelial tissue, including breast, colon and lung.

Scott Tomlins, a MD/PhD graduate student in Dr. Chinnaiyan's laboratory and the lead author of the Science paper, presented the study Tuesday, April 4, at Experimental Biology 2006 in San Francisco. The presentation was part of the scientific program of the American Society for Investigative Pathology (ASIP) held at Experimental Biology, and Mr. Tomlins is the winner of the 2006 ASIP Experimental Pathologist-in-Training Award.

The ETV4 gene is a member of the same family as the two other genes, ETV1 and ERG, reported earlier. All three are ETS genes, a group of approximately 30 genes that encode related transcription factors. Like other family members, ETV4 has a role in normal cell division but is unusually active, or overly expressive, only when it becomes fused with other genes on different chromosomes. Using the same technology as the earlier study, the scientists were able to demonstrate that the ETV4 gene had become fused with another prostate cancer gene on another chromosome.

But the new ETV4 gene has two important differences from the ETV1 and ERG genes. First, while not overexpressed in individuals without prostate cancer, ETV4 is overexpressed in a much smaller fraction of patients with prostate cancer than the malignancy-causing genes described earlier. Second, the over-expressed ETV4 gene appeared in two prostate cancer patients in whom the ETV1 and ERG genes were not overexpressed, suggesting that fusions involving any of the three family members may lead to prostate cancer.

This finding confirms the importance of the ETS gene pathway in causing prostate cancer, say Chinnaiyan and Tomlins. The scientists believe fusions involving these three genes probably account for the majority of prostate cancers.

Citing the power of modern technology, including large gene databases (this study mined the Oncomine database, created by the Chinnaiyan laboratory, for ETS expression in two studies, one from the Chinnaiyan laboratory and the other from Stanford University), bioinformatics approaches that allow the rapid processing of previously unimaginable amounts of information, and an algorithm also created in the Chinnaiyan laboratory, the scientists will continue to look at other components of the ETS pathway, including genes that may get turned on inappropriately but may not be able to be detected through over-expression. Dr. Chinnaiyan also has plans to look for similar gene rearrangements in other solid tumors such as breast cancer.

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