|Researchers Use New Method to Discover Gene Rearrangements
That Can Aid in Detection of Early Prostate Cancer
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.
These findings are the first evidence of non-random, recurrent genetic rearrangements
in epithelial tumors that could lead to research advances in other cancers. However,
these results must be verified in a larger number of tissue samples before actual
detection techniques or therapies can be developed.
The research was supported by the NCI’s EDRN, the NCI’s Specialized Program
of Research Excellence in prostate cancer, the American Cancer Society, the Department
of Defense, and the University of Michigan. The research team included scientists
from the University of Michigan, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Mass., and the University of Ulm, Germany.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.