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Researchers Use New Method to Discover Gene Rearrangements

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A new study, using a unique detection method, has led scientists to identify several genes whose rearrangements in prostate cancer cells may play a role in the development and progression of the disease.

Researchers at the University of Michigan,  Ann Arbor, report that two genes, "ETV1" and "ERG", which previously were implicated as cancer-causing gene rearrangements in Ewing's sarcoma (a relatively rare bone cancer), are now seen as important cancer-causing genes in prostate cancer.

Closer analysis showed how rearrangement of these genes was responsible for their cancer-causing potential. The research appears in the October 28, 2005, issue of "Science" and was supported by the National Cancer Institute (NCI), part of the National Institutes of Health.

This study is the first evidence that non-random, recurrent rearrangements of genes can occur in cancers derived from epithelial cells, which line the body's cavities. Previously, non-random recurrent genetic rearrangements were known to occur only in leukemia, lymphoma, and soft tissue sarcomas.

Gene rearrangements that involve the movement of a gene fragment from one segment of DNA to another, possibly affecting gene expression, (whether a gene is turned on or off), is called a translocation. Gene translocations can have a dramatic effect on gene expression.

One well-known example of a translocation involves the fusion of the "BCR"
gene and the ABL gene. The resulting "BCR-ABL" fusion gene causes the development of chronic myelogenous leukemia. Epithelial tumors, such as prostate cancer, previously have not been known to have such gene changes.

"Studying gene alterations in prostate cancer is difficult," said Jacob Kagan, Ph.D., program director for this study. "As a result there has never been a clear identification of recurrent, non-random genetic rearrangements. This finding is an important advance because it suggests that similar mechanisms may be involved in other epithelial cancers such as breast, lung, and colon."

Researchers began their search for altered genes in prostate cancer cells by analyzing sets of microarray data. Microarray analysis is a method used to measure the expression of all genes in a cell simultaneously. To probe a large amount of microarray data, the scientists developed an innovative step-by-step process, called Cancer Outlier Profile Analysis (COPA), for selection of leading cancer-related over-expressed genes.

COPA takes a vast amount of microarray data and combs it for outliers, or those genes that deviate substantially from the ordinary profile of genes that are expressed in prostate cancer tissues.

COPA data allowed scientists to then identify two new fusion genes, "TMPRSS2-ERG" and "TMPRSS2-ETV1". These genes were formed by fusion of the "TMPRSS2" gene, which is specifically related to the prostate, to the "ERG" or the "ETV1" gene, respectively.

"The finding of a fused gene in prostate cancer is creating a new frontier in developing tests for earlier detection of cancer and molecular targeting," said Sudhir Srivastava, Ph.D., Chief, Cancer Biomarkers Research Program and director of the NCI's Early Detection Research Network (EDRN). "This type of research exemplifies the innovative, forward-looking research goals of the EDRN."

COPA analysis of 221 historical cases (167 tumor and 54 benign prostate tissues samples) showed that either "ERG" or "ETV1" were over-expressed in 95 of the 167 (57 percent) of the tumor samples, while there was no over-expression of either "ERG" or "ETV1" in benign prostate tissue.

In studies done in the labs at the University of Michigan, involving a sample of 22 prostate cancer tissues, 20 (91 percent) showed over-expression of the "ERG" or "ETV1" and also showed fusion with the "TMPRSS2" gene, suggesting that the juxtaposition of "ERG" or "ETV1" to the "TMPRSS2" gene resulted in over-expression of these gene sequences.

"This finding may have important implications for the understanding of the prostate cancer disease process and the development of potential therapies to arrest this process," said lead author of the study, Arul Chinnaiyan, M.D., Ph.D., University of Michigan Medical School, and a principal investigator of the EDRN.